Author: Almeida da Silva, Pedro Eduardo ; Halicki, Priscila Cristina Bartolomeu ; Zanatta, Nilo ; Ramos, Daniela Fernandes ; Pereira, Isabel Ladeira ; de Andrade, Valquíria Pereira

Due to several obstacles in treating tuberculosis (TB), the search for new therapeutic alternatives remains a global priority. The nitrogenous heterocyclic compounds are promising in searching for new anti-Mycobacterium tuberculosis molecules, and our previous results highlight the potential of tetrahydropyridines. After exploring the antimycobacterial potential and putative mechanism of action of a tetrahydropyridine derivative (NUNL02), we seek to measure the oxidative stress caused by NUNL02 inside the extracellular replicating M. tuberculosis since it could be the reason for the NUNL02 bactericidal effect against replicating and starved M. tuberculosis; and to evaluate the anti-M. tuberculosis activity of NUNL02 against the intracellular bacillus (even combined with an anti-TB drug) to explore the potential of this tetrahydropyridine as a promising adjuvant for TB therapy. Briefly, we assessed the activity of NUNL02 against the H₃₇Rv strain and evaluated the combination of NUNL02 and rifampicin (RIF), at previously defined subinhibitory concentrations, against intramacrophage M. tuberculosis. NUNL02, in addition to promote the oxidative stress inside the extracellular replicating M. tuberculosis as a possible indirect mechanism of action, also presented bactericidal potential as promising as RIF against intracellular bacilli. Thus, our findings reinforce NUNL02 as a promising scaffold for the development of new options for TB.

01 Jun 2021·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

2,2,2-trifluoro-1-(1,4,5,6-tetrahydropyridin-3-yl)ethanone derivative as efflux pump inhibitor in Mycobacterium tuberculosis

Q4 · MEDICINE

Article

Author: Vianna, Júlia Silveira ; Almeida da Silva, Pedro Eduardo ; Mateus, Malu ; de Andrade, Valquiria Pereira ; Halicki, Priscila Cristina Bartolomeu ; Ramos, Daniela Fernandes ; Zanatta, Nilo ; de Oliveira, Mariana ; Rodrigues, Virmondes ; da Silva, Marcos Vinicius

Although the administration of combined therapy is efficient to tuberculosis (TB) treatment caused by susceptible Mycobacterium tuberculosis strains, to overcome the multidrug resistance is still a challenge. Some studies have reported evidence about tetrahydropyridines as a putative efflux pump inhibitor, including in mycobacteria, being a promising strategy against M. tuberculosis. Thus, we investigated the biological potential of 2,2,2-trifluoro-1-(1,4,5,6-tetrahydropyridin-3-yl)ethanone derivative (NUNL02) against two strains of M. tuberculosis. NUNL02 was able to increase the susceptibility of the multidrug resistant strain to the anti-TB drugs, resulting in synergism with rifampicin. Still, we assume that this compound plays a role in the efflux mechanism in M. tuberculosis, besides, to be able to kill the bacillus under the deprivation of essential nutrients. Thus, our findings highlight NUNL02 as a promising prototype to develop a new adjuvant for TB treatment, mainly as EPI.

01 Jun 2019·Journal of Global Antimicrobial ResistanceQ3 · MEDICINE

Tetrahydropyridine derivative as efflux inhibitor in Mycobacterium abscessus

Q3 · MEDICINE

Article

Author: Vianna, Júlia S ; Ramos, Daniela F ; Ramis, Ivy B ; Lourenço, Maria Cristina ; Bierhals, Dienefer ; Zanatta, Nilo ; Almeida da Silva, Pedro E ; von Groll, Andrea ; Viveiros, Miguel

OBJECTIVESThis study aimed to evaluate a tetrahydropyridine derivative (THP) as a potential inhibitor of the efflux mechanism and modulator of the high level of antimicrobial resistance usually observed in members of the Mycobacterium abscessus (M. abscessus) group.METHODSThe strain M. abscessus subsp. abscessus (ATCC 19997) was used as reference, in addition to three clinical isolates: M. abscessus subsp. abscessus (AT 07), and two M. abscessus subsp. bolletii (AT 46 and AT 52). The minimum inhibitory concentration (MIC) of amikacin (AMI), ciprofloxacin (CIP), clarithromycin (CLA), verapamil (VP), and THP derivative (NUNL02) was determined.RESULTSThe NUNL02 showed activity against M. abscessus; the MIC of AMI against ATCC 19997 was reduced more than 16-fold, and the MIC of CIP against AT 52 was reduced four-fold. When combined with CLA, the MIC was reduced against all tested strains. In addition, to detect and quantify the activity of the efflux mechanism, the intracellular accumulation kinetics of the fluorometric substrate ethidium bromide in the presence and absence of VP and NUNL02 were evaluated. The NUNL02 was found to be a more effective efflux inhibitor than VP, which is the classical inhibitor.CONCLUSIONSThe tetrahydropyridine derivative, NUNL02, is a promising adjuvant in the treatment of infections caused by M. abscessus.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	Brazil	Universidade Federal do Rio Grande	01 Jun 2021

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