Uncovering an alternate pathway of antibiotic resistance in spore-forming bacteria

Abstract

Spore-forming bacteria produce two distinct cell types: vegetative cells and resilient spores. While antibiotic resistance is typically associated with vegetative cells, spores play a critical role in disseminating resistance genes due to their durability and transmissibility. We previously demonstrated that cephamycin antibiotics target the conserved spore-specific protein SpoVD, significantly reducing spore formation in pathogens including Clostridioides difficile. Here, we show that when C. difficile acquires CdmecA, a homologue of Staphylococcus aureus mecA, one of the most globally burdensome resistance genes, the anti-sporulation effect of cephamycins is bypassed. CdMecA functionally replaces CdSpoVD, restoring sporulation and producing phenotypically distinct spores. We further show that mecA is prevalent across C. difficile strains and other pathogenic, gut, and environmental spore-formers. Since SpoVD is conserved, MecA may broadly co-opt sporulation; we confirm this in Clostridium perfringens. This work reveals an unusual resistance mechanism with unexpected physiological consequences, reshaping our understanding of antibiotic resistance within the context of sporulation and microbial adaptation.

Metadata

Item Type:	Article
Authors/Creators:	Srikhanta, Y.N. Bate, C.E. https://orcid.org/0000-0002-4983-8483 Ng, D. https://orcid.org/0009-0008-5455-8081 Revitt-Mills, S.A. https://orcid.org/0000-0001-7215-6459 Gilmore, G.-R. Williams, G.C. https://orcid.org/0000-0001-9347-7198 Day, S.L. Mesnage, S. https://orcid.org/0000-0003-1648-4890 Kochan, K. Shrestha, S. Shen, A. https://orcid.org/0000-0002-9786-5742 Knight, D.R. https://orcid.org/0000-0002-9480-4733 Imwattana, K. Riley, T.V. https://orcid.org/0000-0002-1351-3740 Alevizos, I. https://orcid.org/0009-0008-8299-0584 Bourke, K. https://orcid.org/0009-0000-1906-4117 Awad, M.M. https://orcid.org/0000-0002-9275-3979 Evans, C.A. https://orcid.org/0000-0003-4356-9216 Siddiqui, G. https://orcid.org/0000-0002-3153-3198 Steele, J.R. https://orcid.org/0000-0002-3070-9761 Steer, D.L. https://orcid.org/0000-0001-5656-1569 Morrow, J.P. Creek, D.J. https://orcid.org/0000-0001-7497-7082 Webb, C. McGowan, S. https://orcid.org/0000-0001-6863-1106 Lyras, D. https://orcid.org/0000-0003-2345-9271
Copyright, Publisher and Additional Information:	© The Author(s) 2026. 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/.
Keywords:	Antibacterial drug resistance; Antimicrobial resistance; Bacteriology; Pathogens
Dates:	Submitted: 4 November 2025 Accepted: 29 June 2026 Published (online): 15 July 2026 Published: 15 July 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Engineering (Sheffield) > School of Chemical, Materials and Biological Engineering The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield)
Funding Information:	Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/M012166/1 MEDICAL RESEARCH COUNCIL MR/S009272/1 BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/W013800/1
Date Deposited:	22 Jul 2026 15:11
Last Modified:	22 Jul 2026 15:11
Status:	Published online
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-026-75594-5
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:243712

CORE (COnnecting REpositories)

Uncovering an alternate pathway of antibiotic resistance in spore-forming bacteria

Abstract

Metadata

Download

Published Version

Export

Statistics