Search for the mechanism of action and therapeutic effect of new classes of drugs against Mycobacterium tuberculosis

• Grant number: 20/13497-4
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2021
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Fernando Rogério Pavan
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Daniele Castagnolo ; Jean Leandro dos Santos
• Associated research grant(s): 23/10762-7 - 58th Conference of the Brazilian Society of Tropical Medicine (MEDTROP 2023), AR.BR

Abstract

Tuberculosis (TB) is one of the 10 leading causes of death in the world and is the disease caused by a single infectious agent with a higher mortality rate, being ahead of HIV/AIDS. Its complex and long treatment, added to the high rate of bacterial resistance, makes it one of the targets pointed out by the World Health Organization along with 12 more bacteria as determinants in the urgency in research and development (R&D) of new antimicrobials. In the last 8 years, we researched different classes of new compounds with possible properties against Mycobacterium tuberculosis and found 7 highly promising compounds, which are: synthetic compounds and benzofuroxan derivatives BZ8, TB10 and TB13, natural compounds tanshinone I, tanshinone IIA and Cryptotanshinone and the complex commercial tris- (1,10-phenanthroline)iron(II). We can divide them into 3 groups, with completely different chemical characteristics, but with high potential within a pipeline to search for new drugs against TB. Alongside these compounds, we developed, together with a group from King's College, a nanocarrier (liposome) functionalized with siderophores and moxifloxacin. At the present moment of the research, we need to understand what is the therapeutic effect of these compounds in models of BALB/c mice and understand the mechanism of action of each one through the complete genomic sequencing (SGC) of naturally resistant mutants. The results obtained in this project, added to all previous studies, will lead to the final outcome of these compounds and the possibility of a new product to be presented to the pharmaceutical industry. (AU)

Scientific publications

(16)

(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)

SOLCIA, MARIANA CRISTINA; CAMPOS, DEBORA LEITE; GRECCO, JULIA ARAUJO; PAIVA SILVA, CAIO SANDER; DA SILVA, PATRICIA BENTO; DA SILVA, ISABEL CRISTIANE; BALDUINO DA SILVA, ANA PAULA; SILVA, JOAS; ODA, FERNANDO BOMBARDA; DOS SANTOS, ANDRE GONZAGA; et al. rowth-inhibitory effects of tris-(1,10-phenanthroline) iron (II) against Mycobacterium tuberculosis in vitro and in viv. TUBERCULOSIS, v. 128, MAY 2021. (20/13497-4, 18/12270-6, 17/12419-7, 16/24633-0, 18/21778-3, 18/12135-1, 18/00163-0)

ROQUE-BORDA, CESAR AUGUSTO; DA SILVA, PATRICIA BENTO; RODRIGUES, MOSAR CORREA; AZEVEDO, RICARDO BENTES; DI FILIPPO, LEONARDO; DUARTE, JONATAS L.; CHORILLI, MARLUS; VICENTE, EDUARDO FESTOZO; PAVAN, FERNANDO ROGERIO. Challenge in the Discovery of New Drugs: Antimicrobial Peptides against WHO-List of Critical and High-Priority Bacteria. PHARMACEUTICS, v. 13, n. 6, JUN 2021. (20/16573-3, 18/25707-3, 20/13497-4)

ROQUE-BORDA, CESAR AUGUSTO; PAVAN, FERNANDO ROGERIO; MENEGUIN, ANDREIA BAGLIOTTI. Pharmaceutical Biotechnology. LIFE-BASEL, v. 12, n. 8, p. 3-pg., 2022-08-01. (20/16573-3, 20/13497-4, 16/00446-7, 18/25707-3)

ROQUE-BORDA, CESAR AUGUSTO; ANTUNES, BRUNA FERNANDES; BORGUES, ANNA BEATRIZ TOLEDO; PONTES, JANAINA TEIXEIRA COSTA DE; MENEGUIN, ANDREIA BAGLIOTTI; CHORILLI, MARLUS; TROVATTI, ELIANE; TEIXEIRA, SILVIO RAINHO; PAVAN, FERNANDO ROGERIO; VICENTE, EDUARDO FESTOZO. Conjugation of Ctx(Ile(21))-Ha Antimicrobial Peptides to Chitosan Ultrathin Films by N-Acetylcysteine Improves Peptide Physicochemical Properties and Enhances Biological Activity. ACS OMEGA, v. 7, n. 32, p. 10-pg., 2022-08-16. (20/16573-3, 20/13497-4, 18/25707-3)

ROQUE-BORDA, CESAR AUGUSTO; DE LIMA GUALQUE, MARCOS WILLIAM; DA FONSECA, FAULLER HENRIQUE; PAVAN, FERNANDO ROGERIO; SANTOS-FILHO, NORIVAL ALVES. Nanobiotechnology with Therapeutically Relevant Macromolecules from Animal Venoms: Venoms, Toxins, and Antimicrobial Peptides. PHARMACEUTICS, v. 14, n. 5, p. 21-pg., 2022-05-01. (20/13497-4, 20/16573-3)

COSTA DE PONTES, JANAINA TEIXEIRA; TOLEDO BORGES, ANNA BEATRIZ; AUGUSTO ROQUE-BORDA, CESAR; PAVAN, FERNANDO ROGERIO. Antimicrobial Peptides as an Alternative for the Eradication of Bacterial Biofilms of Multi-Drug Resistant Bacteria. PHARMACEUTICS, v. 14, n. 3, p. 20-pg., 2022-03-01. (20/16573-3, 20/13497-4)

POLINARIO, GIULIA; PRIMO, LAURA MARIA DURAN GLERIANI; ROSA, MAIARA ALANE BARALDI CERQUETANI; DETT, FREDDY HUMBERTO MARIN; BARBUGLI, PAULA ABOUD; ROQUE-BORDA, CESAR AUGUSTO; PAVAN, FERNANDO ROGERIO. Antimicrobial peptides as drugs with double response against Mycobacterium tuberculosis coinfections in lung cancer. FRONTIERS IN MICROBIOLOGY, v. 14, p. 17-pg., 2023-06-02. (22/09728-6, 20/16573-3, 20/13497-4, 21/14603-5)

FERNANDES, GUILHERME F. S.; MANIERI, KARYN F.; BONJORNO, ANDRESSA F.; CAMPOS, DEBORA L.; RIBEIRO, CAMILA M.; DEMARQUI, FERNANDA M.; RUIZ, DANIEL A. G.; NASCIMENTO-JUNIOR, NAILTON M.; DENNY, WILLIAM A.; THOMPSON, ANDREW M.; et al. Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains. CHEMMEDCHEM, v. 18, n. 12, p. 10-pg., 2023-04-21. (18/00163-0, 18/00187-7, 20/08370-5, 20/13279-7, 18/17739-2, 16/09502-7, 21/14973-7, 20/13497-4)

SOLCIA, MARIANA CRISTINA; CAMPOS, DEBORA LEITE; GRECCO, JULIA ARAUJO; PAIVA SILVA, CAIO SANDER; DA SILVA, PATRICIA BENTO; DA SILVA, ISABEL CRISTIANE; BALDUINO DA SILVA, ANA PAULA; SILVA, JOAS; ODA, FERNANDO BOMBARDA; DOS SANTOS, ANDRE GONZAGA; et al. Growth-inhibitory effects of tris-(1,10-phenanthroline) iron (II) against Mycobacterium tuberculosis in vitro and in vivo. TUBERCULOSIS, v. 128, p. 8-pg., 2021-05-19. (18/00163-0, 16/24633-0, 18/21778-3, 17/12419-7, 18/12270-6, 18/12135-1, 20/13497-4)

MARINGOLO-RIBEIRO, CAMILA; GRECCO, JULIA A.; BELLATO, DEBORA L.; ALMEIDA, ARYADNE L.; BALDIN, VANESSA P.; CALEFFI-FERRACIOLI, KATIANY R.; PAVAN, FERNANDO R.. Rescue of susceptibility to second-line drugs in resistant clinical isolates of Mycobacterium tuberculosis. FUTURE MICROBIOLOGY, v. 17, n. 7, p. 17-pg., 2022-03-23. (18/02344-2, 18/12135-1, 20/13497-4)

LUSTRI, WILTON R.; LAZARINI, SILMARA C.; AQUARONI, NAYARA AP SIMEI; RESENDE, FLAVIA A.; ALEIXO, NADIA A.; PEREIRA, DOUGLAS H.; LUSTRI, BRUNA CARDINALI; MOREIRA, CRISTIANO GALLINA; RIBEIRO, CAMILA M.; PAVAN, FERNANDO R.; et al. A new complex of silver(I) with probenecid: Synthesis, characterization, and studies of antibacterial and extended spectrum beta-lactamases (ESBL) inhibition activities. Journal of Inorganic Biochemistry, v. 243, p. 12-pg., 2023-03-30. (18/00163-0, 19/03049-7, 15/09833-0, 15/20882-3, 18/12062-4, 17/16278-9, 21/07458-9, 17/19243-1, 20/13497-4, 18/12590-0, 19/26696-8, 18/00187-7, 21/08717-8, 18/02344-2)

DE SOUZA, GUILHERME DA COSTA; ROQUE-BORDA, CESAR AUGUSTO; PAVAN, FERNANDO R.. Beta-lactam resistance and the effectiveness of antimicrobial peptides against KPC-producing bacteria. Drug Development Research, v. 83, n. 7, p. 21-pg., 2022-08-30. (21/14603-5, 20/13497-4, 20/16573-3)

ROQUE-BORDA, CESAR AUGUSTO; SOUZA SARAIVA, MAURO DE MESQUITA; MONTE, DANIEL F. M.; RODRIGUES ALVES, LUCAS BOCCHINI; DE ALMEIDA, ADRIANA MARIA; FERREIRA, TAISA SANTIAGO; DE LIMA, TULIO SPINA; PEREIRA BENEVIDES, VALDINETE; CABRERA, JULIA MEMRAVA; CLAIRE, SUNIL; et al. HPMCAS-Coated Alginate Microparticles Loaded with Ctx(Ile(21))-Ha as a Promising Antimicrobial Agent against Salmonella Enteritidis in a Chicken Infection Model. ACS INFECTIOUS DISEASES, v. 8, n. 3, p. 10-pg., 2022-03-11. (20/13497-4, 18/25707-3, 20/16573-3, 16/00446-7)

ROQUE-BORDA, CESAR AUGUSTO; DA SILVA, PATRICIA BENTO; RODRIGUES, MOSAR CORREA; FILIPPO, LEONARDO DELELLO DI; DUARTE, JONATAS L.; CHORILLI, MARLUS; VICENTE, EDUARDO FESTOZO; GARRIDO, SAULO SANTESSO; PAVAN, FERNANDO ROGENIO. Pharmaceutical nanotechnology: Antimicrobial peptides as potential new drugs against WHO list of critical, high, and medium priority bacteria. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 241, p. 18-pg., 2022-08-12. (21/14603-5, 20/13497-4, 20/16573-3, 18/25707-3)

CAMPOS, DEBORA LEITE; DEMARQUI, FERNANDA MANAIA; SOLCIA, MARIANA CRISTINA; DE SOUZA, PAULA CAROLINA; DA SILVA MAIA, PEDRO IVO; DEFLON, VICTOR MARCELO; PAVAN, FERNANDO ROGERIO. Latent Tuberculosis: A Promising New Compound to Treat Non-Replicating and Intramacrophagic Mycobacteria. BIOMEDICINES, v. 10, n. 10, p. 12-pg., 2022-10-01. (20/13497-4, 18/21778-3)

SEMENYA, DOROTHY; TOUITOU, MEIR; MASCI, DOMIZIANA; RIBEIRO, CAMILA MARINGOLO; PAVAN, FERNANDO ROGERIO; FERNANDES, GUILHERME FELIPE DOS SANTOS; GIANIBBI, BEATRICE; MANETTI, FABRIZIO; CASTAGNOLO, DANIELE. Tapping into the antitubercular potential of 2,5-dimethylpyrroles: A structure-activity relationship interrogation. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 237, p. 15-pg., 2022-04-26. (20/13497-4)