Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase

Carola Elisa Heesemann Rosenkilde, Christian Munck, Andreas Porse, Marius Linkevicius, Dan I. Andersson, Morten Otto Alexander Sommer*

*Corresponding author for this work

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Abstract

Antibiotic resistance is a major challenge to global public health. Discovery of new antibiotics is slow and to ensure proper treatment of bacterial infections new strategies are needed. One way to curb the development of antibiotic resistance is to design drug combinations where the development of resistance against one drug leads to collateral sensitivity to the other drug. Here we study collateral sensitivity patterns of the globally distributed extended-spectrum β-lactamase CTX-M-15, and find three non-synonymous mutations with increased resistance against mecillinam or piperacillin–tazobactam that simultaneously confer full susceptibility to several cephalosporin drugs. We show in vitro and in mice that a combination of mecillinam and cefotaxime eliminates both wild-type and resistant CTX-M-15. Our results indicate that mecillinam and cefotaxime in combination constrain resistance evolution of CTX-M-15, and illustrate how drug combinations can be rationally designed to limit the resistance evolution of horizontally transferred genes by exploiting collateral sensitivity patterns.

Original languageEnglish
Article number618
JournalNature Communications
Volume10
Number of pages10
ISSN2041-1723
DOIs
Publication statusPublished - 2019

Keywords

  • Antibiotics
  • Antimicrobial resistance
  • Bacterial evolution
  • Molecular evolution

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