Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales
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.
Authors
- Nicholas Feasey (ORCID: https://orcid.org/0000-0003-4041-1405)
- Joseph M. Lewis (ORCID: https://orcid.org/0000-0002-3837-5188)
- Adam Paul Roberts (ORCID: https://orcid.org/0000-0002-0760-3088)
- Madalitso Mphasa
- Patrick Musicha (ORCID: https://orcid.org/0000-0001-7780-2173)
- Sarah Gallichan (ORCID: https://orcid.org/0000-0001-8938-1628)
- Minh‐Duy Phan (ORCID: https://orcid.org/0000-0002-3426-1044)
- Stephen R. Forrest (ORCID: https://orcid.org/0000-0003-0131-1903)
- Mark A. Schembri (ORCID: https://orcid.org/0000-0003-4863-9260)
- Thomas Edwards (ORCID: https://orcid.org/0000-0003-4058-4461)
- Fabrice E. Graf (ORCID: https://orcid.org/0000-0003-1132-5348)
- Richard N. Goodman (ORCID: https://orcid.org/0009-0008-0578-789X)
- Alasdair T. M. Hubbard (ORCID: https://orcid.org/0000-0001-6668-9179)
- Alice J. Fraser
- Esther Picton-Barlow (ORCID: https://orcid.org/0009-0002-1189-4751)
Institutions
- University of Liverpool (GB)
- The University of Queensland (AU)
- University of St Andrews (GB)
- Liverpool School of Tropical Medicine (GB)
- Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MW)
- Kamuzu University of Health Sciences (MW)
- Nottingham Trent University (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1038/s41467-024-53391-2
- Citations
- 19
- Primary Topic
- Antibiotic Resistance in Bacteria
- Type
- article
- Field-Weighted Citation Impact
- 3.24
Funders
- Oxford Nanopore Technologies
- Joint Programming Initiative on Antimicrobial Resistance
- UK Research and Innovation
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Natural Environment Research Council