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 language | English |
|---|---|
| Article number | 618 |
| Journal | Nature Communications |
| Volume | 10 |
| Number of pages | 10 |
| ISSN | 2041-1723 |
| DOIs | |
| Publication status | Published - 2019 |
Keywords
- Antibiotics
- Antimicrobial resistance
- Bacterial evolution
- Molecular evolution
Cite this
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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 journal › Journal article › Research › peer-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
M1 - 618
ER -