Integration of biophysical and biological approaches to validate fragment-like compounds targeting l,d-transpeptidases from Mycobacterium tuberculosis.

Tuberculosis 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, Ldt

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Copyright © 2023. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gerardo Andrés Libreros Zúñiga reports financial support was provided by Colombian General System of Royalties. Marcio Vinicius Bertacine Dias reports financial support was provided by State of São Paulo Research Foundation. Marcio Vinicius Bertacine Dias reports was provided by National Council for Scientific and Technological Development. Kelly Ishida reports financial support was provided by National Council for Scientific and Technological Development. Rafaela Salgado Ferreira reports financial support was provided by National Council for Scientific and Technological Development. Saulo Fehelberg Pinto Braga reports financial support was provided by Coordination of Higher Education Personnel Improvement. Danilo Pavão e Pavão reports financial support was provided by State of São Paulo Research Foundation. Vinicius de Morais Barroso reports financial support was provided by State of São Paulo Research Foundation. Nathalya C.M.R. Mesquita reports financial support was provided by National Council for Scientific and Technological Development. Glaucius Oliva reports financial support was provided by State of São Paulo Research Foundation.