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.

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.

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.

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.

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.

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.

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.