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Development and search of new antimicrobials against Tuberculosis: from screening to pre-clinical studies in vivo

Abstract

In the last report of the World Health Organization 12 bacteria with high incidence of resistance and more Mycobacterium tuberculosis were determinant in the urgency in research and development (R&D) of new antimicrobials. In 2016 there were 10.4 million new cases of tuberculosis (TB) in the world, of which only 6 million were diagnosed and reported. Resistance to antimicrobials against TB only increases. Currently TB causes more deaths than AIDS and it is estimated that by 2050 deaths from resistant bacterial infections will be the number one cause of death in the world. For more 10 years our group has been developing new strategies to search for new drugs against TB. More than 5,000 compounds from all sources were screened in our laboratory and less than 5% were promising. Among these, we have been able to find a benzofuroxan-derived leader compound that showed excelente activity both in vitro and in vivo and a possible new mechanism of action. As a leading compound we verified the need to improve its activity in resistant bacteria and this is one of the proposals of this project. One the other hand, we understand that nature, as the history of antimicrobials already show us, may be a strategy for a new antibiotic. Thus, as a second strategy we intend to work with more than 60 compounds isolated from plants with known structure and route of synthesis, but never challenged against Mycobaterium tuberculosis. The need for new antimicrobials is urgent, our team is struggling and proposing different strategies to eventually be able to presente a potential new compound for clinical studies. (AU)

Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
POLAQUINI, CARLOS R.; MARQUES, BEATRIZ C.; AYUSSO, GABRIELA M.; MORAO, LUANA G.; SARDI, JANAINA C. O.; CAMPOS, DEBORA L.; SILVA, ISABEL C.; CAVALCA, LUCIA B.; SCHEFFERS, DIRK-JAN; ROSALEN, PEDRO L.; PAVAN, FERNANDO R.; FERREIRA, HENRIQUE; REGASINI, LUIS O. Antibacterial activity of a new monocarbonyl analog of curcumin MAC 4 is associated with divisome disruption. BIOORGANIC CHEMISTRY, v. 109, APR 2021. Web of Science Citations: 0.
FERNANDES, GUILHERME F. S.; CAMPOS, DEBORA L.; DA SILVA, ISABEL C.; PRATES, JOAO L. B.; PAVAN, ALINE R.; PAVAN, FERNANDO R.; DOS SANTOS, JEAN L. Benzofuroxan Derivatives as Potent Agents against Multidrug-Resistant Mycobacterium tuberculosis. CHEMMEDCHEM, v. 16, n. 8 FEB 2021. Web of Science Citations: 0.
SIMEI AQUARONI, NAYARA AP.; NAKAHATA, DOUGLAS H.; LAZARINI, SILMARA C.; RESENDE, FLAVIA A.; CANDIDO, AMANDA L. P.; BARUD, HERNANE DA SILVA; CLARO, AMANDA MARIA; DE CARVALHO, JOAO ERNESTO; RIBEIRO, CAMILA M.; PAVAN, FERNANDO R.; LUSTRI, BRUNA C.; MACHADO RIBEIRO, TAMARA RENATA; MOREIRA, CRISTIANO G.; CANDIDO, TUANY ZAMBROTI; PASSOS LIMA, CARMEN SILVIA; RUIZ, ANA LUCIA T. G.; CORBI, PEDRO P.; LUSTRI, WILTON R. Antibacterial activities and antiproliferative assays over a tumor cells panel of a silver complex with 4-aminobenzoic acid: Studies in vitro of sustained release using bacterial cellulose membranes as support. Journal of Inorganic Biochemistry, v. 212, NOV 2020. Web of Science Citations: 0.
DE SOUZA, P. C.; FERNANDES, G. F. S.; MARINO, L. B.; RIBEIRO, C. M.; DA SILVA, P. B.; CHORILLI, M.; SILVA, C. S. P.; RESENDE, F. A.; SOLCIA, M. C.; DE GRANDIS, R. A.; COSTA, C. A. S.; CHO, S. H.; WANG, Y.; FRANZBLAU, S. G.; DOS SANTOS, J. L.; PAVAN, F. R. Furoxan derivatives demonstrated in vivo efficacy by reducing Mycobacterium tuberculosis to undetectable levels in a mouse model of infection. BIOMEDICINE & PHARMACOTHERAPY, v. 130, OCT 2020. Web of Science Citations: 0.
TOUITOU, MEIR; MANETTI, FABRIZIO; RIBEIRO, CAMILA MARINGOLO; PAVAN, FERNANDO ROGERIO; SCALACCI, NICOLO; ZREBNA, KATARINA; BEGUM, NEELU; SEMENYA, DOROTHY; GUPTA, ANTIMA; BHAKTA, SANJIB; MCHUGH, TIMOTHY D.; SENDEROWITZ, HANOCH; KYRIAZI, MELINA; CASTAGNOLO, DANIELE. Improving the Potency of N-Aryl-2,5-dimethylpyrroles against Multidrug-Resistant and Intracellular Mycobacteria. ACS Medicinal Chemistry Letters, v. 11, n. 5, p. 638-644, MAY 14 2020. Web of Science Citations: 0.
MANZANO, CARLOS M.; NAKAHATA, DOUGLAS H.; TENORIO, JUAN C.; LUSTRI, WILTON R.; RESENDE NOGUEIRA, FLAVIA A.; ALEIXO, NADIA A.; DA SILVA GOMES, PIETRA S.; PAVAN, FERNANDO R.; GRECCO, JULIA A.; RIBEIRO, CAMILA M.; CORBI, PEDRO P. Silver complexes with fluoroanthranilic acid isomers: Spectroscopic characterization, antimycobacterial activity and cytotoxic studies over a panel of tumor cells. Inorganica Chimica Acta, v. 502, MAR 1 2020. Web of Science Citations: 3.
CAMPOS, DEBORA L.; MACHADO, IGNACIO; RIBEIRO, CAMILA M.; GAMBINO, DINORAH; PAVAN, FERNANDO R. Bactericidal effect of pyridine-2-thiol 1-oxide sodium salt and its complex with iron against resistant clinical isolates of Mycobacterium tuberculosis. JOURNAL OF ANTIBIOTICS, v. 73, n. 2, p. 120-124, FEB 2020. Web of Science Citations: 1.
FUMAGALLI, FERNANDO; GIL DE MELO, SHAIANI MARIA; RIBEIRO, CAMILA MARINGOLO; SOLCIA, MARIANA CRISTINA; PAVAN, FERNANDO ROGERIO; EMERY, FLAVIO DA SILVA. Exploiting the furo [2,3-b]pyridine core against multidrug-resistant Mycobacterium tuberculosis. Bioorganic & Medicinal Chemistry Letters, v. 29, n. 8, p. 974-977, APR 15 2019. Web of Science Citations: 0.
DE GRANDIS, RONE APARECIDO; DA SILVA DOS SANTOS, PATRICK WELLINGTON; DE OLIVEIRA, KATIA MARA; TOMAZELA MACHADO, ANA RITA; AISSA, ALEXANDRE FERRO; BATISTA, ALZIR AZEVEDO; GREGGI ANTUNES, LUSANIA MARIA; PAVAN, FERNANDO ROGERIO. Novel lawsone-containing ruthenium(II) complexes: Synthesis, characterization and anticancer activity on 2D and 3D spheroid models of prostate cancer cells. BIOORGANIC CHEMISTRY, v. 85, p. 455-468, APR 2019. Web of Science Citations: 3.

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