Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase.
Amdinocillin
/ pharmacology
Animals
Anti-Bacterial Agents
/ pharmacology
Cefotaxime
/ pharmacology
Disease Models, Animal
Drug Combinations
Drug Resistance, Microbial
/ genetics
Escherichia coli
/ drug effects
Female
Gene Transfer, Horizontal
/ drug effects
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Mutation
beta-Lactamases
/ drug effects
beta-Lactams
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 02 2019
06 02 2019
Historique:
received:
22
10
2018
accepted:
15
01
2019
entrez:
8
2
2019
pubmed:
8
2
2019
medline:
12
4
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30728359
doi: 10.1038/s41467-019-08529-y
pii: 10.1038/s41467-019-08529-y
pmc: PMC6365502
doi:
Substances chimiques
Anti-Bacterial Agents
0
Drug Combinations
0
beta-Lactams
0
beta-lactamase CTX-M-15
EC 3.5.2.-
beta-Lactamases
EC 3.5.2.6
Cefotaxime
N2GI8B1GK7
Amdinocillin
V10579P3QZ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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