Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center, Szeged, Hungary.
Mol Syst Biol. 2013 Oct 29;9:700. doi: 10.1038/msb.2013.57.
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.
抗生素耐药性的演变常常伴随着对多种其他抗菌药物的耐药性增加。相比之下，人们对协同敏感性的频率和机制知之甚少。在这种情况下，抗生素压力下的遗传适应性会导致对其他抗生素的敏感性增强。通过使用大肠杆菌的大规模实验室进化实验，我们证明了在抗生素耐药性的进化过程中协同敏感性经常发生。具体来说，适应氨基糖苷类抗生素的种群在存在几种其他抗生素时的适应性特别低。实验室进化菌株的全基因组测序揭示了氨基糖苷类耐药性的多种机制，包括内膜质子动力势（PMF）的降低。我们提出，作为副作用，这些突变会降低 PMF 依赖性主要外排泵（包括 AcrAB 转运蛋白）的活性，导致对几种其他抗生素的敏感性增加。更一般地说，我们的工作深入了解了在抗生素选择下驱动负权衡进化的机制。
