IMBIV   05474
INSTITUTO MULTIDISCIPLINARIO DE BIOLOGIA VEGETAL
Unidad Ejecutora - UE
artículos
Título:
Identification of the potential biological target of N -benzenesulfonyl-1,2,3,4-tetrahydroquinoline compounds active against gram-positive and gram-negative bacteria
Autor/es:
MARTINEZ, SOL R.; BECERRA, MARÍA C.; PAVANI, CHRISTIANE C.; QUEVEDO, MARIO A.; BAPTISTA, MAURICIO S.; RIBONE, SERGIO R.
Revista:
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Editorial:
ADENINE PRESS
Referencias:
Año: 2019 p. 1 - 10
ISSN:
0739-1102
Resumen:
The development of new antibiotics with activity towards a broad spectrum of bacteria,including multiresistant strains, is a very important topic for global public health. As part ofprevious works, N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline (BSTHQ) derivatives weredescribed as antimicrobial agents active against Gram-positive and Gram-negative pathogens.In this work, experimental and molecular modelling studies were performed in order toidentify their potential biological target in the light of structure-based design efforts towardsfurther BSTHQ derivatives. First, a carboxyfluorescein leakage assay was performed usingliposomes to mimic bacterial membranes, which found no significative membrane disruptioneffects with respect to control samples. These results support a non-surfactant antimicrobialactivity of the tested compounds. In a second stage, the inhibition of potential antimicrobialtargets was screened using molecular modelling methods, taking into account previouslyreported druggable targets deposited in the ChEMBL database for Escherichia coli andStaphylococcus aureus. Two enzymes, namely D-glutamic acid-adding enzyme (MurD) andN-acetylglucosamine-1-phophate-uridyltransferase (GlmU), both involved in bacterialmembrane synthesis, were identified as potential targets. Pharmacodynamic interactionmodels were developed using known MurD and GlmU inhibitors by applying state-of-the-artchemoinformatic methods (molecular docking, molecular dynamics and free energy ofinteraction analyses). These models were further extended to the analysis of the studiedBSTHQ derivatives. Overall, our results demonstrated that the studied BSTHQ derivativeselicit their antibacterial activity by interacting with a specific molecular target, GlmU beingthe highly feasible one. Based on the presented results, further structure-aided design effortstowards the obtaining of novel BSTHQ derivatives are envisioned.