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

## TL;DR

Researchers developed non-toxic polymyxin derivatives that enhance the effectiveness of antibiotics against drug-resistant Gram-negative bacteria.

## Contribution

The study introduces non-nephrotoxic polymyxin B3 derivatives that synergize with multiple antibiotics to combat MDR bacteria.

## Key findings

- Compound 1 is non-toxic and synergizes with six antibiotic classes against MDR Gram-negative bacteria.
- Compound 1 lowers the minimum inhibitory concentrations of rifampicin, zoliflodacin, and pristinamycin.
- The combination of zoliflodacin and compound 1 shows potent bactericidal activity in MDR P. aeruginosa and A. baumannii.

## Abstract

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 1, 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 1 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 Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. Notably, the novel combination of zoliflodacin, a first-in-class antibiotic in phase III trials for gonorrhea, and compound 1 exhibited potent bactericidal activity in MDR P. aeruginosa and A. baumannii.