# C7-Substituted Quinolines as Potent Inhibitors of AdeG Efflux Pumps in Acinetobacter baumannii

## TL;DR

Scientists developed new quinoline compounds that block bacterial efflux pumps, helping antibiotics work better against resistant Acinetobacter baumannii.

## Contribution

The study introduces C7-substituted quinolines as potent and selective inhibitors of AdeG efflux pumps in Acinetobacter baumannii.

## Key findings

- C7-substituted quinolines significantly inhibited efflux pumps and potentiated chloramphenicol in Acinetobacter baumannii.
- Compounds 1.3 and 3.3 showed up to 64-fold potentiation of chloramphenicol.
- The compounds selectively inhibited AdeFGH over AdeABC and showed no toxicity in a Galleria mellonella model.

## Abstract

Efflux, mediated by a series of multidrug efflux pumps,
is a major
contributor to antibiotic resistance in Gram-negative bacteria. Efflux
pump inhibitors (EPIs), which can block efflux, have the potential
to be used as adjuvant therapies to resensitize bacteria to existing
antibiotics. In this study, 36 quinoline-based compounds were synthesized
as potential EPIs targeting resistance nodulation division (RND) family
pumps in the multidrug-resistant pathogen Acinetobacter
baumannii. In A. baumannii strains with overexpressed AdeFGH (chloramphenicol-adapted)
and AdeABC (AYE, Ab5075-UW), these compounds enhanced Hoechst dye
accumulation, indicating general efflux inhibition, and potentiated
chloramphenicol, which is an AdeG substrate. The research focused
on two generations of quinoline compounds, with modifications at the
C-7 position of first-generation compounds to improve hydrophobic
interactions with the Phe loop in the AdeG efflux pump, to generate
second-generation compounds. The modified quinolines showed strong
pump inhibition and significant chloramphenicol potentiation, with
MIC reductions of 4- to 64-fold. Notably, compounds 1.8 and 3.8 exhibited the highest inhibitory activity,
while compounds 1.3 and 3.3 showed up to
64-fold potentiation, highlighting the importance of specific structural
features at the C-7 position for efflux pump inhibition. The study
also revealed selective inhibition of AdeFGH over AdeABC, with no
potentiation observed for gentamicin, showing the specificity of these
quinoline-based inhibitors. Importantly, the compounds showed no toxicity
in a Galleria mellonella model at a
dose level of 20 mg/kg, highlighting their suitability as potential
antibiotic adjuvants for combating bacterial resistance.