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

Detalhes bibliográficos
Autor(a) principal: Olivença, Francisco
Data de Publicação: 2022
Outros Autores: Nunes, Alexandra, Macedo, Rita, Pires, David, Silveiro, Cátia, Anes, Elsa, Miragaia, Maria, Gomes, João Paulo, Catalão, Maria João
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.18/8472
Resumo: Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9431576/
id RCAP_8b2b71be75e5a3c3b199cc8ffb9ac9fc
oai_identifier_str oai:repositorio.insa.pt:10400.18/8472
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome SequencingMycobacterium tuberculosisAntibiotic RepurposingBeta-lactamsDrug ResistanceWhole-genome SequencingInfecções RespiratóriasResistência aos AntimicrobianosFree PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9431576/The 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.This 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.).American Society for MicrobiologyRepositório Científico do Instituto Nacional de SaúdeOlivença, FranciscoNunes, AlexandraMacedo, RitaPires, DavidSilveiro, CátiaAnes, ElsaMiragaia, MariaGomes, João PauloCatalão, Maria João2023-01-30T13:46:29Z2022-06-132022-06-13T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/8472engMicrobiol Spectr. 2022 Aug 31;10(4):e0067422. doi: 10.1128/spectrum.00674-22. Epub 2022 Jun 13.2165-049710.1128/spectrum.00674-22info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:35Zoai:repositorio.insa.pt:10400.18/8472Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:43:06.412954Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
title Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
spellingShingle Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
Olivença, Francisco
Mycobacterium tuberculosis
Antibiotic Repurposing
Beta-lactams
Drug Resistance
Whole-genome Sequencing
Infecções Respiratórias
Resistência aos Antimicrobianos
title_short Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
title_full Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
title_fullStr Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
title_full_unstemmed Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
title_sort Uncovering Beta-Lactam Susceptibility Patterns in Clinical Isolates of Mycobacterium tuberculosis through Whole-Genome Sequencing
author Olivença, Francisco
author_facet Olivença, Francisco
Nunes, Alexandra
Macedo, Rita
Pires, David
Silveiro, Cátia
Anes, Elsa
Miragaia, Maria
Gomes, João Paulo
Catalão, Maria João
author_role author
author2 Nunes, Alexandra
Macedo, Rita
Pires, David
Silveiro, Cátia
Anes, Elsa
Miragaia, Maria
Gomes, João Paulo
Catalão, Maria João
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Nacional de Saúde
dc.contributor.author.fl_str_mv Olivença, Francisco
Nunes, Alexandra
Macedo, Rita
Pires, David
Silveiro, Cátia
Anes, Elsa
Miragaia, Maria
Gomes, João Paulo
Catalão, Maria João
dc.subject.por.fl_str_mv Mycobacterium tuberculosis
Antibiotic Repurposing
Beta-lactams
Drug Resistance
Whole-genome Sequencing
Infecções Respiratórias
Resistência aos Antimicrobianos
topic Mycobacterium tuberculosis
Antibiotic Repurposing
Beta-lactams
Drug Resistance
Whole-genome Sequencing
Infecções Respiratórias
Resistência aos Antimicrobianos
description Free PMC article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9431576/
publishDate 2022
dc.date.none.fl_str_mv 2022-06-13
2022-06-13T00:00:00Z
2023-01-30T13:46:29Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.18/8472
url http://hdl.handle.net/10400.18/8472
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Microbiol Spectr. 2022 Aug 31;10(4):e0067422. doi: 10.1128/spectrum.00674-22. Epub 2022 Jun 13.
2165-0497
10.1128/spectrum.00674-22
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799132176753623040

Registros relacionados