Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii.

Gregory A Knauf,Ashley L Cunningham,Vincent Cattoir,M Stephen Trent,Bryan W Davies,Alexander A Crofts,Ian M Riddington,Misha I Kazi,John J Mekalanos

doi:10.1128/mbio.02394-17

Abstract

ABSTRACTQuaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. While they are known for their membrane-damaging properties, QAC action has been suggested to extend beyond the surface to intracellular targets. Here we characterize the range of action of the QAC biocide benzalkonium chloride (BZK) against the bacterial pathogen Acinetobacter baumannii. At high concentrations, BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. Resistance to BZK is found to develop through ribosomal protein mutations that protect A. baumannii against BZK-induced protein aggregation. The multifunctional impact of BZK led us to discover that alternative QAC structures, with low human toxicity, retain potent action against multidrug-resistant A. baumannii, Staphylococcus aureus, and Clostridium difficile and present opportunities for their development as antibiotics.

Highlights

Quaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria
Several studies indicate that QACs have intracellular effects that contribute to their antimicrobial action, with the critical lethal action being dependent on the exposure concentration [8,9,10,11,12,13,14,15,16,17]
With this expanded mechanistic understanding, we demonstrate that alternative QAC structures, with low toxicity, still retain their antimicrobial action, opening new scaffolds for design of antibiotics and treatment of multidrug-resistant bacteria

Summary

Introduction

Quaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. While at high concentrations BZK acts primarily through membrane damage, we show that at low concentrations disruption of cellular protein homeostasis (proteostasis) is associated with A. baumannii cell death. With this expanded mechanistic understanding, we demonstrate that alternative QAC structures, with low toxicity, still retain their antimicrobial action, opening new scaffolds for design of antibiotics and treatment of multidrug-resistant bacteria

Methods

Results

Conclusion