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

Research output: Contribution to journalJournal articleResearchpeer-review

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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

Cite this

@article{96997fff66f344c79f42f39b8cb38438,
title = "Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase",
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.",
keywords = "Antibiotics, Antimicrobial resistance, Bacterial evolution, Molecular evolution",
author = "Rosenkilde, {Carola Elisa Heesemann} and Christian Munck and Andreas Porse and Marius Linkevicius and Andersson, {Dan I.} and Sommer, {Morten Otto Alexander}",
year = "2019",
doi = "10.1038/s41467-019-08529-y",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase. / Rosenkilde, Carola Elisa Heesemann; Munck, Christian; Porse, Andreas; Linkevicius, Marius; Andersson, Dan I.; Sommer, Morten Otto Alexander.

In: Nature Communications, Vol. 10, 618, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase

AU - Rosenkilde, Carola Elisa Heesemann

AU - Munck, Christian

AU - Porse, Andreas

AU - Linkevicius, Marius

AU - Andersson, Dan I.

AU - Sommer, Morten Otto Alexander

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Antibiotics

KW - Antimicrobial resistance

KW - Bacterial evolution

KW - Molecular evolution

U2 - 10.1038/s41467-019-08529-y

DO - 10.1038/s41467-019-08529-y

M3 - Journal article

VL - 10

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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ER -