Enhancing the Potency of Nalidixic Acid toward a Bacterial DNA Gyrase with Conjugated Peptides

Quinolones and fluoroquinolones are widely used antibacterial agents. 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.