The evolutionary mechanism of non-carbapenemase carbapenem-resistant phenotypes in Klebsiella spp

作者：Natalia C. Rosas, Jonathan J. Wilksch, Jake Barber, Jiahui Li, Yanan Wang, Zhewei Sun, Andrea Rocker, Chaille T. Webb, Laura Perlaza-Jiménez, Christopher J. Stubenrauch, Dhanasekaran Vijaykrishna, Jiangning Song, George Taiaroa, Mark R. Davies, Richard A. Strugnell, Qiyu Bao, Tieli Zhou, Michael J. McDonald, Trevor Lithgow · 发表于：eLife · 年份：2023 · DOI：10.7554/elife.83107 · 被引用次数：19 · 研究领域：Antibiotic Resistance in Bacteria、Genomics and Phylogenetic Studies、Evolution and Genetic Dynamics

Antibiotic resistance is driven by selection, but the degree to which a bacterial strain’s evolutionary history shapes the mechanism and strength of resistance remains an open question. Here, we reconstruct the genetic and evolutionary mechanisms of carbapenem resistance in a clinical isolate of Klebsiella quasipneumoniae . A combination of short- and long-read sequencing, machine learning, and genetic and enzymatic analyses established that this carbapenem-resistant strain carries no carbapenemase-encoding genes. Genetic reconstruction of the resistance phenotype confirmed that two distinct genetic loci are necessary in order for the strain to acquire carbapenem resistance. Experimental evolution of the carbapenem-resistant strains in growth conditions without the antibiotic revealed that both loci confer a significant cost and are readily lost by de novo mutations resulting in the rapid evolution of a carbapenem-sensitive phenotype. To explain how carbapenem resistance evolves via multiple, low-fitness single-locus intermediates, we hypothesised that one of these loci had previously conferred adaptation to another antibiotic. Fitness assays in a range of drug concentrations show how selection in the antibiotic ceftazidime can select for one gene ( bla DHA-1 ) potentiating the evolution of carbapenem resistance by a single mutation in a second gene ( ompK36 ). These results show how a patient’s treatment history might shape the evolution of antibiotic resistance and could ex...