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Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing

2022-06-13Journal article Open access
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dc.contributor.authorOlivença, Francisco
dc.contributor.authorNunes, Alexandra
dc.contributor.authorMacedo, Rita
dc.contributor.authorPires, David
dc.contributor.authorSilveiro, Cátia
dc.contributor.authorAnes, Elsa
dc.contributor.authorMiragaia, Maria
dc.contributor.authorGomes, João Paulo
dc.contributor.authorCatalão, Maria João
dc.date.accessioned2023-01-30T13:46:29Z
dc.date.available2023-01-30T13:46:29Z
dc.date.issued2022-06-13
dc.descriptionFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9431576/pt_PT
dc.description.abstractThe increasing threat of drug resistance and a stagnated pipeline of novel therapeutics endanger the eradication of tuberculosis. Beta-lactams constitute promising additions to the current therapeutic arsenal and two carbapenems are included in group C of medicines recommended by the WHO for use in longer multidrug-resistant tuberculosis regimens. However, the determinants underlining diverse Mycobacterium tuberculosis phenotypes to beta-lactams remain largely undefined. To decipher these, we present a proof-of-concept study based on a large-scale beta-lactam susceptibility screening for 172 M. tuberculosis clinical isolates from Portugal, including 72 antimycobacterial drug-resistant strains. MICs were determined for multiple beta-lactams and strains were subjected to whole-genome sequencing to identify core-genome single-nucleotide variant-based profiles. Global and cell wall-targeted approaches were then followed to detect putative drivers of beta-lactam response. We found that drug-resistant strains were more susceptible to beta-lactams, but significant differences were not observed between distinct drug-resistance profiles. Sublineage 4.3.4.2 strains were significantly more susceptible to beta-lactams, while the contrary was observed for Beijing and 4.1.2.1 sublineages. While mutations in beta-lactamase or cell wall biosynthesis genes were uncommon, a rise in beta-lactam MICs was detected in parallel with the accumulation of mutations in peptidoglycan cross-linking or cell division genes. Finally, we exposed that putative beta-lactam resistance markers occurred in genes for which relevant roles in cell wall processes have been ascribed, such as rpfC or pknA. Genetic studies to validate the relevance of the identified mutations for beta-lactam susceptibility and further improvement of the phenotype-genotype associations are needed in the future. IMPORTANCE Associations between differential M. tuberculosis beta-lactam phenotypes and preexisting antimycobacterial drug resistance, strain sublineage, or specific mutational patterns were established. Importantly, we reveal that highly drug-resistant isolates of sublineage 4.3.4.2 have an increased susceptibility to beta-lactams compared with other strains. Thus, directing beta-lactams to treat infections by specific M. tuberculosis strains and refraining its use from others emerges as a potentially important strategy to avoid resistance development. Individual mutations in blaC or genes encoding canonical beta-lactam targets, such as peptidoglycan transpeptidases, are infrequent and do not greatly impact the MICs of potent carbapenem plus clavulanic acid combinations. An improved understanding of the global effect of cumulative mutations in relevant gene sets for peptidoglycan and cell division processes on beta-lactam susceptibility is also provided.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e Tecnologia (PTDC/BIA-MIC/31233/2017 to M.J.C, SFRH/BD/136853/2018 to F.O. and 2021.05446.BD to C.S.) and by the European Society of Clinical Microbiology and Infectious Diseases (Research Grant 2018 to M.J.C.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMicrobiol Spectr. 2022 Aug 31;10(4):e0067422. doi: 10.1128/spectrum.00674-22. Epub 2022 Jun 13.pt_PT
dc.identifier.doi10.1128/spectrum.00674-22pt_PT
dc.identifier.issn2165-0497
dc.identifier.urihttp://hdl.handle.net/10400.18/8472
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Society for Microbiologypt_PT
dc.relationClinical significance of Mycobacterium tuberculosis cell wall structural diversity: contribution to novel mechanisms of antibiotic resistance and relevance towards tuberculosis progression and treatment.
dc.relationNovo: Deciphering unexploited features of drug-repurposing beta-lactams against tuberculosis: from genomic patterns of Mycobacterium tuberculosis susceptibility to synergistic combinations. Inicial: Decoding the peptidoglycan patterns associated with beta-lactams susceptibility and host immune recognition in drug-resistant Mycobacterium tuberculosis
dc.relation.publisherversionhttps://journals.asm.org/doi/10.1128/spectrum.00674-22pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMycobacterium tuberculosispt_PT
dc.subjectAntibiotic Repurposingpt_PT
dc.subjectBeta-lactamspt_PT
dc.subjectDrug Resistancept_PT
dc.subjectWhole-genome Sequencingpt_PT
dc.subjectInfecções Respiratóriaspt_PT
dc.subjectResistência aos Antimicrobianospt_PT
dc.titleUncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleClinical significance of Mycobacterium tuberculosis cell wall structural diversity: contribution to novel mechanisms of antibiotic resistance and relevance towards tuberculosis progression and treatment.
oaire.awardTitleNovo: Deciphering unexploited features of drug-repurposing beta-lactams against tuberculosis: from genomic patterns of Mycobacterium tuberculosis susceptibility to synergistic combinations. Inicial: Decoding the peptidoglycan patterns associated with beta-lactams susceptibility and host immune recognition in drug-resistant Mycobacterium tuberculosis
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-MIC%2F31233%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F136853%2F2018/PT
oaire.citation.issue4pt_PT
oaire.citation.startPagee0067422pt_PT
oaire.citation.titleMicrobiology Spectrumpt_PT
oaire.citation.volume10pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamOE
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationf643b1c7-8a5c-41b7-b673-927f686741ac
relation.isProjectOfPublicationb654dc7a-b65a-4eb0-a346-e79b49cc5e16
relation.isProjectOfPublication.latestForDiscoveryf643b1c7-8a5c-41b7-b673-927f686741ac

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