Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Jonathan Wilksch
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Centre to Impact AMR, Monash University, Clayton, Australia; School of Biological Sciences, Monash University, Clayton, Australia
Jiahui Li
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Yanan Wang
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; School of Biological Sciences, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia
Zhewei Sun
Wenzhou Medical University, Wenzhou, China
Andrea Rocker
Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Chaille T Webb
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Laura Perlaza-Jiménez
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
Centre to Impact AMR, Monash University, Clayton, Australia; School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
Jiangning Song
Centre to Impact AMR, Monash University, Clayton, Australia; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
George Taiaroa
Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Melbourne, Australia
Mark Davies
Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Melbourne, Australia
Richard A Strugnell
Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne, Melbourne, Australia
Qiyu Bao
Wenzhou Medical University, Wenzhou, China
Tieli Zhou
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Centre to Impact AMR, Monash University, Clayton, Australia; School of Biological Sciences, Monash University, Clayton, Australia
Trevor Lithgow
Centre to Impact AMR, Monash University, Clayton, Australia; Infection Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia
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 (blaDHA-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 explain the genetic basis of carbapenem-resistance found in many enteric-pathogens.
