Bacterial evolution of antibiotic hypersensitivity

Molecular Systems Biology

Viktória Lázár³  Gajinder Pal Singh³  Réka Spohn³  István Nagy¹  Balázs Horváth¹  Mónika Hrtyan³  Róbert Busa-Fekete²  Balázs Bogos³  Orsolya Méhi³  Bálint Csörgő³  György Pósfai³  Gergely Fekete³  Balázs Szappanos³  Balázs Kégl²  Balázs Papp³ 

[1] Genomics Unit, Institute of Biochemistry, Biological Research Center, Szeged, Hungary;Linear Accelerator Laboratory, University of Paris-Sud, CNRS, Orsay, France;Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center, Szeged, Hungary

关键词: antibiotic resistance;    collateral sensitivity network;    evolutionary experiment;    trade off;   

DOI  :  10.1038/msb.2013.57

来源: Wiley

【 摘 要 】

Abstract

The evolution of resistance to a single antibiotic is frequently accompanied by increased resistance to multiple other antimicrobial agents. In sharp contrast, very little is known about the frequency and mechanisms underlying collateral sensitivity. In this case, genetic adaptation under antibiotic stress yields enhanced sensitivity to other antibiotics. Using large-scale laboratory evolutionary experiments with Escherichia coli, we demonstrate that collateral sensitivity occurs frequently during the evolution of antibiotic resistance. Specifically, populations adapted to aminoglycosides have an especially low fitness in the presence of several other antibiotics. Whole-genome sequencing of laboratory-evolved strains revealed multiple mechanisms underlying aminoglycoside resistance, including a reduction in the proton-motive force (PMF) across the inner membrane. We propose that as a side effect, these mutations diminish the activity of PMF-dependent major efflux pumps (including the AcrAB transporter), leading to hypersensitivity to several other antibiotics. More generally, our work offers an insight into the mechanisms that drive the evolution of negative trade-offs under antibiotic selection.

Synopsis

Understanding how adaptation to a given antibiotic increases the sensitivity to other antibiotics is of great medical importance for the understanding of evolutionary trade-offs. Here, the first experimental map of such collateral sensitivity is presented, along with insights into the underlying mechanisms.

• Large-scale laboratory evolution experiments revealed that evolution of resistance to a single antibiotic frequently yields enhanced sensitivity to other antibiotics (collateral sensitivity).
• Specifically, genetic adaptation to aminoglycosides increased the sensitivity to many other classes of antibiotics.
• Whole-genome sequencing of laboratory-evolved strains demonstrated that aminoglycoside resistance is partly achieved through reduction in the proton-motive force (PMF). As a side effect, the corresponding mutations diminish the activity of PMF-dependent major efflux pumps, leading to antibiotic hypersensitivity.

【 授权许可】

CC BY-NC-SA   
Copyright © 2013 EMBO and Macmillan Publishers Limited

Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation without specific permission.