Noncytotoxic polymyxin derivatives enhance antibiotic action against multidrug-resistant Gram-negative bacteria

The widespread emergence of multidrug-resistant (MDR) Gram-negative bacteria prompted the reintroduction of polymyxins in the clinic despite their adverse effects. Ongoing research is primarily focused on the development of non-nephrotoxic and -neurotoxic polymyxins as not only standalone agents but also as potentiators that enhance the activity of a partner antibiotic. Safer derivatives of polymyxin B₃, a minor component of polymyxin B, were synthesized and utilized as a potentiator of multiple antibiotics. Compound <b>1</b>, consisting of Dap residues, was nontoxic to kidney cells and is a promising outer membrane permeabilizer that synergized with six different classes of antibiotics against MDR Gram-negative bacteria. Compound <b>1</b> extended the activity spectrum of rifampicin, zoliflodacin, and pristinamycin by lowering the minimum inhibitory concentrations of these antibiotics below their interpretative susceptibility breakpoints in MDR <i>Pseudomonas aeruginosa</i>, <i>Acinetobacter baumannii</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Enterobacter cloacae</i>. Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound <b>1</b> exhibited potent bactericidal activity in MDR <i>P. aeruginosa</i> and <i>A. baumannii</i>.