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

Carola E. H. Rosenkilde, Christian Munck, Andreas Porse, Marius Linkevicius, Dan I. Andersson and Morten O. A. Sommer ()
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Carola E. H. Rosenkilde: Technical University of Denmark
Christian Munck: Technical University of Denmark
Andreas Porse: Technical University of Denmark
Marius Linkevicius: Uppsala University, Box 582
Dan I. Andersson: Uppsala University, Box 582
Morten O. A. Sommer: Technical University of Denmark

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08529-y

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