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Deciphering unexploited features of drug-repurposing beta-lactams against tuberculosis : from genomic patterns of Mycobacterium tuberculosis susceptibility to synergistic combinations

2024-03Doctoral thesis Open access
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datacite.subject.fosCiências Naturais::Ciências Biológicaspt_PT
dc.contributor.advisorCatalão, Maria João Gracias Fernandes da Costa
dc.contributor.advisorAnes, Elsa Maria Ribeiro dos Santos
dc.contributor.advisorGomes, João Paulo dos Santos
dc.contributor.authorOlivença, Francisco
dc.date.accessioned2025-02-07T17:14:16Z
dc.date.available2025-02-07T17:14:16Z
dc.date.issued2024-03
dc.date.submitted2023-12
dc.description.abstractTuberculosis (TB) still figures as one of the leading death causes by a single infectious agent worldwide. The natural capacity of Mycobacterium tuberculosis (Mtb) to evade and subvert host immune responses, coupled with the increasing threat of drug-resistant TB (DR-TB), contribute to the difficult containment of this infection. Alternative treatment options for DR-TB are desperately required, either by identification of novel antimicrobials or by repurposing existing drugs. Through an approach focused on the essential nature of the peptidoglycan, a core layer of the cell wall, this work aims to reevaluate presumed paradigms behind the historically restricted use of beta-lactams in TB and to unveil new dimensions of the effects of this class against the causative agent. The results of a large-scale beta-lactam susceptibility screening in clinical Mtb isolates corroborate previous observations, with the majority of the strains displaying low minimum inhibitory concentrations to carbapenems combined with clavulanate. Furthermore, correlation of these results with whole-genome sequencing data allowed us to show that drug-resistant strains of one of the main sublineages circulating in Portugal were more susceptible to beta-lactams. Acquired mycobacterial resistance to inhibitors of peptidoglycan synthesis was addressed in parallel in the reference strains Mtb H37Rv and Mycolicibacterium smegmatis mc2 -155. Beta-lactamase or peptidoglycan transpeptidase genes were mostly conserved and mutations arose in genes encoding lesser-known lipoproteins with predicted penicillin-binding activity or transcription regulators. The extracellular and intracellular interactions between beta-lactams and conventional antimycobacterials were also explored, revealing a promising synergistic effect between meropenem/clavulanate and the first-line antibiotic ethambutol. In addition to the antimicrobial effect, subsequent experiments indicated that this combination may also impair the concealment of the peptidoglycan to a greater extent than the individual antibiotics, potentially threatening pathogen evasion and survival. This comprehensive study supports the activity of specific beta-lactams against Mtb. The outputs contribute to an integrated understanding of the rational application of this well-characterized class in TB, in alignment with the WHO END TB goals of maximizing favorable clinical outcomes and suppressing disease burden.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2025-02-03T13:00:36Z No. of bitstreams: 1 scnd990026354741941_td_Francisco_Miguel.pdf: 13175308 bytes, checksum: 9036ec5d52886bd8beb4cf1b6c89a516 (MD5)en
dc.description.provenanceMade available in DSpace on 2025-02-07T17:14:16Z (GMT). No. of bitstreams: 1 scnd990026354741941_td_Francisco_Miguel.pdf: 13175308 bytes, checksum: 9036ec5d52886bd8beb4cf1b6c89a516 (MD5) Previous issue date: 2024-03en
dc.identifier.tid101700423pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.5/98221
dc.language.isoengpt_PT
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.subjecttuberculosept_PT
dc.subjectMycobacterium tuberculosispt_PT
dc.subjectresistência antimicrobianapt_PT
dc.subjectantibióticos beta-lactâmicospt_PT
dc.subjectreposicionamento de fármacospt_PT
dc.subjecttuberculosispt_PT
dc.subjectantimicrobial resistancept_PT
dc.subjectbeta-lactam antibioticspt_PT
dc.subjectdrug-repurposingpt_PT
dc.titleDeciphering unexploited features of drug-repurposing beta-lactams against tuberculosis : from genomic patterns of Mycobacterium tuberculosis susceptibility to synergistic combinationspt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
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/OE/SFRH%2FBD%2F136853%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//COVID%2FBD%2F153212%2F2023/PT
oaire.fundingStreamOE
person.familyNameOlivença Miguel
person.givenNameFrancisco
person.identifier.ciencia-id171D-63E7-8A66
person.identifier.orcid0000-0001-7973-2631
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.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
relation.isAuthorOfPublication14d73d22-9cad-43d9-99c7-7307548b0066
relation.isAuthorOfPublication.latestForDiscovery14d73d22-9cad-43d9-99c7-7307548b0066
relation.isProjectOfPublication20892763-25eb-42e6-a67d-069578b99005
relation.isProjectOfPublication2eec26b2-5bc1-4034-806d-b67f1a0fdad8
relation.isProjectOfPublication.latestForDiscovery20892763-25eb-42e6-a67d-069578b99005
thesis.degree.nameTese de doutoramento, Farmácia (Microbiologia), Universidade de Lisboa, Faculdade de Farmácia, 2024pt_PT

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