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Effects of CwlM, a peptidoglycan synthesis regulator, on beta-lactam tolerance and host-pathogen interactions

2026-01-01Artigo de investigação Acesso aberto
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dc.contributor.authorSilveiro, Cátia
dc.contributor.authorMortinho, Diana
dc.contributor.authorOlivença, Francisco
dc.contributor.authorMandal, Manoj
dc.contributor.authorPires, David
dc.contributor.authorAnes, Elsa
dc.contributor.authorCatalão, Maria João
dc.date.accessioned2026-01-27T14:51:18Z
dc.date.available2026-01-27T14:51:18Z
dc.date.issued2026-01-01
dc.description.abstractBackground: The emergence and spread of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (Mtb) urge the development of novel drugs and efficient therapeutic programs. A recent study aiming to uncover differential beta-lactam susceptibility phenotypes in clinical strains of Mtb found that the M237V substitution in cwlM (Rv3915) was associated with increased susceptibility to amoxicillin. Considering that Mycobacterium smegmatis (Msm) is a widely used surrogate model for Mtb, we constructed a cwlM knockdown mutant in Msm using CRISPR interference (CRISPRi) to elucidate the role of CwlM in beta-lactam susceptibility and intracellular survival. Results: Quantitative RT-PCR assays confirmed the successful repression of cwlM, while the phenotyping assays confirmed the essentiality of CwlM-related processes for mycobacterial growth. Collectively, the antibiotic susceptibility assays suggested that CwlMSMEG may contribute to increased tolerance to meropenem and cefotaxime. Moreover, CwlMSMEG was found to support M. smegmatis survival within THP-1-derived macrophages. To address conflicting reports regarding its predicted peptidoglycan (PG) hydrolase activity, we purified recombinant CwlMTB. The Micrococcus luteus-derived PG-based zymogram indicated that CwlMTB lacks PG-hydrolytic activity, suggesting it might act as a regulator of PG biosynthesis instead. Conclusions: Our findings indicate that CwlM contributes to beta-lactam tolerance and intracellular survival, regardless of lacking detectable PG-hydrolytic activity. Overall, CwlM was found to be essential and highly vulnerable, highlighting its potential as a therapeutic target that warrants further investigation.eng
dc.identifier.citationSilveiro, C., Mortinho, D., Olivença, F., & Mandal, M. et al. (2026). Effects of CwlM, a peptidoglycan synthesis regulator, on beta-lactam tolerance and host-pathogen interactions. BMC Microbiology, 26(1), Article 21. https://doi.org/10.1186/s12866-025-04548-6
dc.identifier.doi10.1186/s12866-025-04548-6
dc.identifier.eid105027322008
dc.identifier.issn1471-2180
dc.identifier.other7a15791c-f651-4934-bd9e-60bc94f8afd6
dc.identifier.pmcPMC12797351
dc.identifier.pmid41354769
dc.identifier.urihttp://hdl.handle.net/10400.14/56798
dc.identifier.wos001660451100001
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAntibiotic tolerance
dc.subjectBeta-lactams
dc.subjectCRISPR interference
dc.subjectHost-pathogen interactions
dc.subjectPeptidoglycan biosynthesis
dc.subjectTuberculosis
dc.titleEffects of CwlM, a peptidoglycan synthesis regulator, on beta-lactam tolerance and host-pathogen interactionseng
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.issue1
oaire.citation.titleBMC Microbiology
oaire.citation.volume26
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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