Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 Oct 2024
18 Oct 2024
Historique:
received:
15
02
2024
accepted:
10
10
2024
medline:
19
10
2024
pubmed:
19
10
2024
entrez:
18
10
2024
Statut:
epublish
Résumé
Infections with Enterobacterales (E) are increasingly difficult to treat due to antimicrobial resistance. After ceftriaxone replaced chloramphenicol (CHL) as empiric therapy for suspected sepsis in Malawi in 2004, extended-spectrum beta-lactamase (ESBL)-E rapidly emerged. Concurrently, resistance to CHL in Escherichia coli and Klebsiella spp. decreased, raising the possibility of CHL re-introduction. However, many phenotypically susceptible isolates still carry CHL acetyltransferase (cat) genes. To understand the molecular mechanisms and stability of this re-emerging CHL susceptibility we use a combination of genomics, phenotypic susceptibility assays, experimental evolution, and functional assays for CAT activity. Here, we show that of 840 Malawian E. coli and Klebsiella spp. isolates, 31% have discordant CHL susceptibility genotype-phenotype, and we select a subset of 42 isolates for in-depth analysis. Stable degradation of cat genes by insertion sequences leads to re-emergence of CHL susceptibility. Our study suggests that CHL could be reintroduced as a reserve agent for critically ill patients with ESBL-E infections in Malawi and similar settings and highlights the ongoing challenges in inferring antimicrobial resistance from sequence data.
Identifiants
pubmed: 39424629
doi: 10.1038/s41467-024-53391-2
pii: 10.1038/s41467-024-53391-2
doi:
Substances chimiques
beta-Lactamases
EC 3.5.2.6
Anti-Bacterial Agents
0
Chloramphenicol
66974FR9Q1
Chloramphenicol O-Acetyltransferase
EC 2.3.1.28
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9019Subventions
Organisme : Unilever
ID : MA-2021-00523N
Organisme : Unilever
ID : MA-2021-00523N
Organisme : Unilever
ID : MA-2021-00523N
Organisme : Unilever
ID : MA-2021-00523N
Organisme : Unilever
ID : MA-2021-00523N
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/N013514/1
Organisme : Research Councils UK (RCUK)
ID : MR/W030578/1
Organisme : Research Councils UK (RCUK)
ID : 107136
Organisme : Research Councils UK (RCUK)
ID : 107136
Organisme : Research Councils UK (RCUK)
ID : 107136
Organisme : Research Councils UK (RCUK)
ID : MR/W030578/1
Organisme : Research Councils UK (RCUK)
ID : 107136
Organisme : Research Councils UK (RCUK)
ID : 107136
Informations de copyright
© 2024. The Author(s).
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