Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales

Graf, F.E., Goodman, R.N., Gallichan, S., Forrest, S., Picton-Barlow, E., Fraser, A.J., Phan, M.-D., Mphasa, M., Hubbard, A.T.M. ORCID: 0000-0001-6668-9179, Musicha, P., Schembri, M.A., Roberts, A.P., Edwards, T., Lewis, J.M. and Feasey, N.A., 2024. Molecular mechanisms of re-emerging chloramphenicol susceptibility in extended-spectrum beta-lactamase-producing Enterobacterales. Nature Communications, 15: 9019. ISSN 2041-1723

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Abstract

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.

Item Type: Journal article
Publication Title: Nature Communications
Creators: Graf, F.E., Goodman, R.N., Gallichan, S., Forrest, S., Picton-Barlow, E., Fraser, A.J., Phan, M.-D., Mphasa, M., Hubbard, A.T.M., Musicha, P., Schembri, M.A., Roberts, A.P., Edwards, T., Lewis, J.M. and Feasey, N.A.
Publisher: Springer
Date: 18 October 2024
Volume: 15
ISSN: 2041-1723
Identifiers:
NumberType
10.1038/s41467-024-53391-2DOI
2268695Other
Rights: © the author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Divisions: Schools > School of Science and Technology
Record created by: Jonathan Gallacher
Date Added: 30 Oct 2024 15:40
Last Modified: 30 Oct 2024 15:40
URI: https://irep.ntu.ac.uk/id/eprint/52486

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