Banca de DEFESA: JONATHAM SOUZA MOREIRA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : JONATHAM SOUZA MOREIRA
DATA : 08/03/2021
HORA: 09:00
LOCAL: Virtual
TÍTULO:

EVALUATION OF A SERIES OF THYOSEMICARBAZONES AS INHIBITORS OF NEW DHELI METALLO-BETA-LACTAMASE-1

 

PALAVRAS-CHAVES:

NDM; Beta Lactamases, Antimicrobial resistance, Thiosemicarbazones

PÁGINAS: 78
GRANDE ÁREA: Ciências da Saúde
ÁREA: Farmácia
SUBÁREA: Análise Toxicológica
RESUMO:

In recent years, the global spread of bacterial resistance to β-lactam drugs has been observed, with carbapenem derivatives having an important role in the treatment of infections by multi-resistant bacteria. The expression of β-lactamase is mainly related to bacterial resistance, which requires the development of bacterial resistance blockers. Although combinations of β-lactam drugs and serine-β-lactamase inhibitors have been successful, such inhibitors are inactive against Metalo-β-lactamases especially, New Delhi Metalo-β-lactamase (NDM). So far, few compounds are active against NDM-producing bacteria and no specific inhibitors are available. A rational development strategy for NDM inhibitors begins with in vitro assays with the aim of identifying compounds that can act synergistically with β-lactam antibiotics. Thus, thiosemicarbazone derivatives were synthesized and investigated for their ability to reverse the NDM-resistant phenotype in Enterobacter cloacae. Phenotypic screening indicated that four beta-isatin-thiosemicarbazones showed Fractional Inhibitory Concentration (FIC) ≤ 250 µM in the presence of Meropenem (2 µg/mL) with compound 17, the most promising, (FIC = 31.25 µM) showing an effect synergistic (FIC index = 0.34). Docking and Molecular Dynamics studies on NDM-compound 17 complex suggested that 2,3-dihydro-1H-indol-2-one subunit of isatin-β interacts with catalytic zinc and performs hydrogen bonds with Asp-124 acting as a non-classical bioisostere of carboxylic acid. In addition, the tautomeric state of thiosemicarbazone with oxidized sulfur appears to act as a spacer instead of a zinc chelator and the aromatic portions are stabilized by pi-pi and pi-cation interactions with His189 and Lys221 residues. Our results addressed some structural characteristics of thiosemicarbazone in complex with NDM, and highlights its scaffold as promising alternatives to face bacterial resistance.

MEMBROS DA BANCA:
Presidente - 1187203 - JOICE NEVES REIS PEDREIRA
Interno(a) - 1528081 - DARIZY FLAVIA SILVA AMORIM DE VASCONCELOS
Externo(a) à Instituição - FRANCO HENRIQUE ANDRADE LEITE