Integration of biophysical and biological approaches to validate fragment-like compounds targeting L,D-transpeptidases from Mycobacterium tuberculosis

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Autor(es): dc.contributorUniversidade de São Paulo (USP)-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.contributorUniversity of Valle-
Autor(es): dc.contributorUniversidade Federal de Minas Gerais (UFMG)-
Autor(es): dc.contributorUniversity of Warwick-
Autor(es): dc.creatorAndrés Libreros-Zúñiga, Gerardo-
Autor(es): dc.creatorPavão e Pavão, Danilo-
Autor(es): dc.creatorde Morais Barroso, Vinicius-
Autor(es): dc.creatorCristina de Moraes Roso Mesquita, Nathalya-
Autor(es): dc.creatorFehelberg Pinto Braga, Saulo-
Autor(es): dc.creatorOliva, Glaucius-
Autor(es): dc.creatorSalgado Ferreira, Rafaela-
Autor(es): dc.creatorIshida, Kelly-
Autor(es): dc.creatorVinicius Bertacine Dias, Marcio-
Data de aceite: dc.date.accessioned2025-08-21T15:42:45Z-
Data de disponibilização: dc.date.available2025-08-21T15:42:45Z-
Data de envio: dc.date.issued2025-04-29-
Data de envio: dc.date.issued2023-12-31-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.1016/j.bioorg.2023.106960-
Fonte completa do material: dc.identifierhttps://hdl.handle.net/11449/296983-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/296983-
Descrição: dc.descriptionTuberculosis is one of the major causes of death worldwide; more than a million people die every year because of this infection. The constant emergency of Mycobacterium tuberculosis resistant strains against the most used treatments also contributes to the burden caused by this disease. Consequently, the development of new alternative therapies against this disease is constantly required. In recent years, only a few molecules have reached the market as new antituberculosis agents. The mycobacterial cell wall biosynthesis is for a longstanding considered an important target for drug development. Particularly, in M. tuberculosis, the peptidoglycan cross-links are predominantly formed by nonclassical bridges between the third residues of adjacent tetrapeptides. The responsible enzymes for these reactions are LD-transpeptidases (Ldts), for which M. tuberculosis has five paralogues. Although these enzymes are distinct from the penicillin-binding proteins (PBPs), they can also be inactivated by β-lactam antibiotics, but since M. tuberculosis has a chromosomal β-lactamase, most of the antibiotics of these classes can be degraded. Thus, to identify alternative scaffolds for the development of new antimicrobials against tuberculosis, we have integrated several fragment-based drug discovery techniques. Based on that, we identified and validated a number of small molecules that could be the starting point in the synthesis of more potent inhibitors against at least two Ldts from M. tuberculosis, LdtMt2 and LdtMt3. Eight identified molecules inhibited the Ldts activity in at least 20%, and three of them have antimycobacterial activity. The cell ultrastructural analysis suggested that one of the best compounds induced severe effects on the septum and cell wall morphologies, which corroborates our target-based approach to identifying new Ldts hits.-
Descrição: dc.descriptionDepartment of Microbiology Institute of Biomedical Science University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo-
Descrição: dc.descriptionIBILCE São Paulo State University, Rua Cristóvão Colombo, 2265, São Paulo-
Descrição: dc.descriptionDepartment of Microbiology Faculty of Health University of Valle, Calle 4B # 36-00, 760043, Valle del Cauca-
Descrição: dc.descriptionInstitute of Physics of São Carlos University of São Paulo, Av. João Dagnone, 1100 - Jardim Santa Angelina-
Descrição: dc.descriptionDepartment of Biochemistry and Immunology Institute of Biological Sciences Federal University of Minas Gerais. Av. Antônio Carlos, 6627 - Belo Horizonte-
Descrição: dc.descriptionDepartment of Chemistry University of Warwick-
Descrição: dc.descriptionIBILCE São Paulo State University, Rua Cristóvão Colombo, 2265, São Paulo-
Idioma: dc.languageen-
Relação: dc.relationBioorganic Chemistry-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectFragment-based drug discovery-
Palavras-chave: dc.subjectL,D-Transpeptidases-
Palavras-chave: dc.subjectMycobacterium tuberculosis-
Palavras-chave: dc.subjectTuberculosis-
Título: dc.titleIntegration of biophysical and biological approaches to validate fragment-like compounds targeting L,D-transpeptidases from Mycobacterium tuberculosis-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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