Broad-Spectrum Activity of Peptide-Linked Amikacin Conjugates in Synergy with Polymyxin B against Extensively Drug-Resistant and Pandrug-Resistant Bacteria

Global dissemination of genes conferring carbapenem and aminoglycoside resistance has put <i>Klebsiella</i> at the top of the World Health Organization's list of critical priority pathogens. The burgeoning arsenal of aminoglycoside modifying enzymes (AMEs) and 16S rRNA methyltransferases (RMTases) threatens to render aminoglycosides ineffective. Drug combination therapy such as polymyxin and aminoglycoside amikacin has been indicated for drug-resistant <i>Klebsiella</i> infections. The goal of this study was to chemically synthesize and study the antibacterial activity for a novel peptide-linked amikacin library combined with polymyxin. Amikacin derivatives with amino acids containing a positive charge, containing sulfur or with aromatic side chains, were synergistic with polymyxin B against amikacin and pandrug-resistant bacteria. Of 31 <i>Klebsiella pneumoniae</i> strains screened with amikacin peptides containing tryptophan and cysteine with polymyxin, synergy was observed in 77% of strains, including those carrying multiple AME and RMTases. P-AMK compounds behave similarly to AMK, with or without PMB, in killing mammalian cells, but are much more synergistic (as compared to AMK) with PMB in killing drug-resistant bacterial cells.