# Broad-Spectrum Naphthyl-Substituted Diaminoquinolines Inhibiting the AdeG Efflux Pump of Acinetobacter baumannii

## TL;DR

This study shows that certain chemicals can block two types of antibiotic resistance pumps in a harmful bacteria, improving the effectiveness of antibiotics.

## Contribution

Naphthyl-substituted diaminoquinolines inhibit both AdeFGH and AdeIJK efflux pumps in Acinetobacter baumannii.

## Key findings

- Inhibitors potentiate antibacterial activities of various antibiotics in A. baumannii strains.
- Amino acid substitutions in AdeG affect efflux properties and inhibitor sensitivity.
- Inhibitors interact similarly in deep binding pockets but differ in proximal sites.

## Abstract

AdeFGH and AdeIJK,
the two homologous multidrug efflux pumps of
the resistance-nodulation-division superfamily of transporters, play
distinct roles in Acinetobacter baumannii physiology and antibiotic resistance. Unlike ubiquitous AdeIJK,
AdeFGH is strain-specific, typically expressed at low levels, and
if overproduced, it enables resistance to a narrow spectrum of antibiotics,
e.g., fluoroquinolones or chloramphenicol. In this study, we report
that representatives of naphthyl-substituted diaminoquinolines targeting
AdeIJK are also active against AdeFGH. We isolated AdeFGH-overproducing
strains from the clinical AYE and Ab5075 isolates lacking AdeIJK and
AdeABC pumps and demonstrated that these inhibitors are active in A. baumannii strains with different genetic backgrounds.
The inhibitors potentiate the antibacterial activities of various
antibiotics and enhance the bactericidal properties of the fluoroquinolones.
We further analyzed how amino acid substitutions in the substrate
translocation tunnels of AdeG affect the efflux properties of this
pump and its sensitivity to inhibitors and compared them to the analogous
substitutions in AdeJ. Our results suggest that the inhibitors engage
similar contacts within the deep binding pockets of the two pumps
but differ in their interactions in the entrance and the proximal
binding sites. We conclude that the broad-spectrum activities of the
diaminoquinolines as well as other inhibitors likely arise from the
interactions within the deep-binding pockets, but their specificity
is determined in the proximal-binding sites of the pumps.