Frameshift mutation (690delG) in cpxA contributes to the extensive drug resistance of a Serratia marcescens clinical isolate.

Victor Gravrand, Frédéric Ariey, Laura Terracol, Hélène Poupet, Alexandra Doloy, Claire Poyart, Hedi Mammeri

The Journal of antimicrobial chemotherapy 2022 May 29

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To identify the genetic change responsible for resistance to penicillins, extended-spectrum cephalosporins (ESCs), aminoglycosides and ciprofloxacin in a Serratia marcescens clinical isolate recovered from a pancreatic abscess 6 weeks after a WT strain was isolated from the same patient. The impact on the fitness was also assessed. The genomes of both S. marcescens isolates were sequenced using Illumina technology, assembled, annotated and compared with each other. PCR amplification followed by Sanger sequencing was carried out to confirm the mutation. Complementation of the resistant isolate with a recombinant plasmid harbouring the WT gene was performed. The growth rates were measured for both isolates in LB medium. Comparative genomic analysis disclosed only one frameshift mutation (690delG) in the cpxA gene, which codes for the histidine kinase of a two-component system (TCS). This change introduced a premature termination codon, leading to the truncated CpxA_HatR variant that contained 234 amino acids instead of 464. Complementation, which consisted of transfer of the WT cpxA into the resistant S. marcescens derivative, restored completely its susceptibility to ESCs, aminoglycosides and ciprofloxacin, thus confirming the contribution of the CpxA_HatR variant to resistance. Growth analysis showed that the fitness of the resistant isolate was unchanged. This study shows for the first time that constitutive activation of the Cpx pathway can per se confer resistance to ESCs and ciprofloxacin, in addition to the aminoglycoside resistance usually described. It sheds new light on the role of altered TCSs in fostering bacterial survival. © The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Citation

Victor Gravrand, Frédéric Ariey, Laura Terracol, Hélène Poupet, Alexandra Doloy, Claire Poyart, Hedi Mammeri. Frameshift mutation (690delG) in cpxA contributes to the extensive drug resistance of a Serratia marcescens clinical isolate. The Journal of antimicrobial chemotherapy. 2022 May 29;77(6):1611-1616