Drug Information
General Information of This Drug
| Drug ID | DRG00300 | |||||
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| Drug Name | Nalidixic Acid | |||||
| Synonyms |
nalidixic acid; 389-08-2; Nalidixate; Nalidixin; NegGram; Nevigramon; Uronidix; Innoxalon; Nalidixan; Nalitucsan; Sicmylon; Unaserus; Nalidic acid; Nalidixinic acid; Wintomylon; Dixiben; Dixinal; Jicsron; Nalurin; Naxuril; Cybis; Nalix; Nogram; Urisal; Uroman; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid; Betaxina; Kusnarin; Nalidicron; Nicelate; Specifen; Specifin; Urodixin; Narigix; Negram; Poleon; Uralgin; Uriben; Uriclar; Uroneg; Uropan; Naldixic acid; Acide nalidixique; Acide nalidixico; Acido nalidixico; WIN 18,320; Acidum nalidixicum; NSC-82174; Eucistin; 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; Acido nalidissico; Nalidixane; NCI-C56199; 1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; 3-Carboxy-1-ethyl-7-methyl-1,8-naphthyridin-4-one; 1,4-Dihydro-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid; 1,8-Naphthyridine-3-carboxylic acid, 1-ethyl-1,4-dihydro-7-methyl-4-oxo-; 3-Carboxy-1-ethyl-7-methyl-1,8-naphthidin-4-one; MFCD00006884; CCRIS 2365; Acide nalidixique [INN-French]; Acido nalidixico [INN-Spanish]; Acidum nalidixicum [INN-Latin]; HSDB 3241; 1-Ethyl-7-methyl-1,4-dihydro-1,8-naphthyridin-4-one-3-carboxylic acid; EINECS 206-864-7; UNII-3B91HWA56M; WIN-18320; 1-Aethyl-7-methyl-1,8-naphthyridin-4-on-3-karbonsaeure; BRN 0750515; 3B91HWA56M; DTXSID3020912; CHEBI:100147; NSC82174; Acide 1-etil-7-metil-1,8-naftiridin-4-one-3-carbossilico; Nalidixic acid (NegGram); DTXCID70912; MLS000028504; Win 18320; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid; 5-25-07-00384 (Beilstein Handbook Reference); NCGC00018181-08; SMR000058264; Wintron; Nalidixic acid [USAN:USP:INN:BAN:JAN]; 1,4-Dihydro-1-ethyl-7-methyl-1,8-naphthyridin-4-one-3-carboxylic acid; Acid, Nalidixic; Nalidixic acid 100 microg/mL in Acetonitrile; Acido nalidissico [DCIT]; Acide nalidixico [Italian]; Acide nalidixique [French]; NALIDIXIC ACID (MART.); NALIDIXIC ACID [MART.]; Acide nalidixique (INN-French); Acido nalidixico (INN-Spanish); Acidum nalidixicum (INN-Latin); 1-Ethyl-7-methyl-1,8-naphthyridin-4-one-3-carboxylic acid; Nalidixic; NALIDIXIC ACID (EP IMPURITY); NALIDIXIC ACID [EP IMPURITY]; NALIDIXIC ACID (USP IMPURITY); NALIDIXIC ACID [USP IMPURITY]; 1,8-Naphthyridine-3-carboxylic acid,1-ethyl-1,4-dihydro-7-methyl-4-oxo-; CAS-389-08-2; Nalidixic acid (USAN:USP:INN:BAN:JAN); NegGram (TN); wil 18,320; Innoxalomn; Nalidixinsaure; Eucisten; nalidixic-acid; SR-01000003086; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-(1,8)naphthyridine-3-carboxylic acid; 1-Aethyl-7-methyl-1,8-naphthyridin-4-on-3-karbonsaeure [German]; Acide 1-etil-7-metil-1,8-naftiridin-4-one-3-carbossilico [Italian]; NALIDIXICACID; WIN 183203; CHEMBL5; Spectrum_000918; Maybridge1_007101; Opera_ID_1064; Prestwick0_000187; Prestwick1_000187; Prestwick2_000187; Prestwick3_000187; Spectrum2_001360; Spectrum3_000075; Spectrum4_000817; Spectrum5_001540; Nalidixic acid, >=98%; UPCMLD-DP129; N-1200; NALIDIXIC ACID [MI]; NCIOpen2_004342; Lopac0_000837; Oprea1_010545; SCHEMBL21736; BSPBio_000113; BSPBio_001889; KBioGR_001333; KBioSS_001398; NALIDIXIC ACID [INN]; NALIDIXIC ACID [JAN]; MLS001148578; MLS002303041; MLS004820190; MLS006011875; 1-ethyl-7-methyl-4-oxo-1; BIDD:GT0529; DivK1c_000058; NALIDIXIC ACID [HSDB]; NALIDIXIC ACID [USAN]; SPECTRUM1500756; SPBio_001579; SPBio_002034; NALIDIXIC ACID [VANDF]; BPBio1_000125; NALIDIXIC ACID [WHO-DD]; UPCMLD-DP129:001; BDBM21691; GTPL12773; HMS500C20; HMS561K17; KBio1_000058; KBio2_001398; KBio2_003966; KBio2_006534; KBio3_001109; J01MB02; NINDS_000058; HMS1921G10; HMS2092K04; HMS2232H24; HMS3259O13; HMS3374G11; HMS3656K05; Pharmakon1600-01500756; Nalidixic acid (JP17/USP/INN); Nalidixic acid, analytical standard; ALBB-021275; HY-B0398; Tox21_110835; Tox21_201477; Tox21_302754; BBL012279; CCG-39298; NALIDIXIC ACID [ORANGE BOOK]; NSC757432; STK735579; 1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxilic acid; AKOS000120074; Tox21_110835_1; DB00779; NC00494; NSC-757432; SDCCGSBI-0050814.P004; IDI1_000058; NCGC00018181-01; NCGC00018181-02; NCGC00018181-03; NCGC00018181-04; NCGC00018181-05; NCGC00018181-06; NCGC00018181-07; NCGC00018181-09; NCGC00018181-10; NCGC00018181-12; NCGC00018181-13; NCGC00021730-03; NCGC00021730-04; NCGC00021730-05; NCGC00021730-06; NCGC00021730-07; NCGC00256581-01; NCGC00259028-01; AS-13289; NCI60_041807; SMR004703506; SY049448; WLN: T66 BN EV JNJ B2 DVQ I1; Nalidixic acid 100 microg/mL in Methanol; SBI-0050814.P003; DB-049349; Nalidixic acid 1000 microg/mL in Methanol; 1, 1-ethyl-1,4-dihydro-7-methyl-4-oxo-; FT-0603390; N0490; NS00009829; S2328; SW219624-1; 1-Ethyl-1,8-naphthyridine-3-carboxilic acid; 1-Ethyl-1,8-naphthyridine-3-carboxylic acid; EN300-20573; VU0239598-6; C05079; D00183; D91720; Nalidixic acid, meets USP testing specifications; Q281082; SR-01000003086-4; SR-01000003086-6; BRD-K47886988-323-03-0; Nalidixic acid, Antibiotic for Culture Media Use Only; SR-01000003086-10; F0850-6751; Z104478940; 3-CARBOXY-1-ETHYL-7-METHYL-1,8-NAPTHIDIN-4-ONE; 1-ethyl-7-methyl-4-oxo-[1,8]naphthyridine-3-carboxylic acid; Nalidixic acid, European Pharmacopoeia (EP) Reference Standard; Nalidixic acid, United States Pharmacopeia (USP) Reference Standard; 1-ETHYL-7-METHYL-1,4-DIHYDRO-1,8-NAPTHYRIDIN-4-ONE-CARBOXYLIC ACID; 1-Ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid; 1-ETHYL-1,4-DIHYDRO-7-METHYL-4-OXO-1,8-NAPTHYRIDINE-3-CARBOXYLIC ACID; 1-ETHYL-7-METHYL-4-OXO-1,4-DIHYDRO[1,8]NAPHTHYRIDINE-3-CARBOXYLIC ACID; InChI=1/C12H12N2O3/c1-3-14-6-9(12(16)17)10(15)8-5-4-7(2)13-11(8)14/h4-6H,3H2,1-2H3,(H,16,17
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| Structure |
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| Formula |
C12H12N2O3
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| #Ro5 Violations (Lipinski): 0 | Molecular Weight (mw) | 232.23 | ||||
| Lipid-water partition coefficient (xlogp) | 1.4 | |||||
| Hydrogen Bond Donor Count (hbonddonor) | 1 | |||||
| Hydrogen Bond Acceptor Count (hbondacc) | 5 | |||||
| Rotatable Bond Count (rotbonds) | 2 | |||||
| PubChem CID | ||||||
| Canonical smiles |
CCN1C=C(C(=O)C2=C1N=C(C=C2)C)C(=O)O
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| InChI |
InChI=1S/C12H12N2O3/c1-3-14-6-9(12(16)17)10(15)8-5-4-7(2)13-11(8)14/h4-6H,3H2,1-2H3,(H,16,17)
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| InChIKey |
MHWLWQUZZRMNGJ-UHFFFAOYSA-N
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| IUPAC Name |
1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid
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Full Information of The Activity Data of The PDC(s) Related to This Drug
XRRR - Nalidixic acid conjugate [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | . Not detected | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | . Not detected | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | > 80 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | > 80 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | > 800 μM | |||
| Administration Time | 2 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus infection strain | 1280 | ||
XRXRXRX - Nalidixic acid conjugate [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 13 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 13 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 6.0 ± 0.1 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 7 ± 2 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 25 μM | |||
| Administration Time | 2 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus infection strain | 1280 | ||
RXRXRX - Nalidixic acid conjugate [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 18 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 18 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 6.0 ± 3.3 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 7.0 ± 1.4 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 25 μM | |||
| Administration Time | 2 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus infection strain | 1280 | ||
| Experiment 6 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | > 80 μM | |||
| Evaluation Method | CCK-8 assay | ||||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
To assess whether our most potent NA-peptide conjugates would possess a therapeutic window compatible with low levels of human toxicity, two types of human fibroblasts were treated with NA, compound 4, and the unconjugated peptide. The IC50 values were >10-fold higher for the fibroblasts versus the S. aureus strains tested. This trend indicates that the drug conjugates may possess a suitable therapeutic window for successful application as antibacterial agents.
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| In Vitro Model | Normal | Human fibroblast strain 1 | Homo sapiens | ||
| Experiment 7 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | > 80 μM | |||
| Evaluation Method | CCK-8 assay | ||||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
To assess whether our most potent NA-peptide conjugates would possess a therapeutic window compatible with low levels of human toxicity, two types of human fibroblasts were treated with NA, compound 4, and the unconjugated peptide. The IC50 values were >10-fold higher for the fibroblasts versus the S. aureus strains tested. This trend indicates that the drug conjugates may possess a suitable therapeutic window for successful application as antibacterial agents.
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| In Vitro Model | Normal | Human fibroblast strain 2 | Homo sapiens | ||
FRARXRARXRAR - Nalidixic acid conjugate [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 37 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 147 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 20 ± 2 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 61 ± 2 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 200 μM | |||
| Administration Time | 2 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus infection strain | 1280 | ||
RXRX - Nalidixic acid conjugate [Investigative]
Revealed Based on the Cell Line Data
| Experiment 1 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 68 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 2 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Minimum inhibitory concentration (MIC) | 74 μg/mL | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 3 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 52 ± 1 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
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| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 4 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 57 ± 0.8 μM | |||
| Administration Time | 24 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
|
||||
| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
|
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus | 1280 | ||
| Experiment 5 Reporting the Activity Data of This PDC | [1] | ||||
| Indication | <i>Staphylococcus aureus</i> infection | ||||
| Efficacy Data | Half maximal inhibitory concentration (IC50) | 800 μM | |||
| Administration Time | 2 h | ||||
| MOA of PDC |
Nalidixic acid (NA) is a first-generation quinolone-based antibiotic that has a narrow spectrum and poor pharmacokinetics. Here, we describe a family of peptide-nalidixic acid conjugates featuring different levels of hydrophobicity and molecular charge prepared by solid-phase peptide synthesis that exhibit intriguing improvements in potency. In comparison to NA, which has a low level of potency in S. aureus, the NA peptide conjugates with optimized hydrophobicities and molecular charges exhibited significantly improved antibacterial activity. The most potent NA conjugate-featuring a peptide containing cyclohexylalanine and arginine-exhibited efficient bacterial uptake and, notably, specific inhibition of S. aureus DNA gyrase. A systematic study of peptide-NA conjugates revealed that a fine balance of cationic charge and hydrophobicity in an appendage anchored to the core of the drug is required to overcome the intrinsic resistance of S. aureus DNA gyrase toward this quinolone-based drug.
Click to Show/Hide
|
||||
| Description |
As expected, unconjugated NA showed limited activity toward MRSA and MSSA. Peptide vectors alone did not show significant toxicity to both MRSA and MSSA at all concentrations investigated. However, several of the peptide/drug conjugates, compounds 4 and 5 in particular, exhibited much lower IC50 and MIC values in both strains of the bacteria. A comparison of the hydrophobicities and molecular charges of the peptide/drug conjugates indicates that these two properties exert significant influence over the activities of these molecules. Hydrophobicity, measured by monitoring HPLC elution profiles, increased in the following order: 2 6 < 3 &tide; 4 < 5. The peptide conjugates that exhibited the highest potencies, compounds 4 and 5, had the highest levels of hydrophobicity. Compound 3, which had a similar level of hydrophobicity relative to these compounds, exhibited a lower level of toxicity, indicating that hydrophobicity alone does not control activity. This compound also carries a lower molecular charge, pointing to this parameter as another influencer of potency.
Click to Show/Hide
|
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| In Vitro Model | Staphylococcus aureus infection | Staphylococcus aureus infection strain | 1280 | ||
References