Identification of the potential biological target of N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline compounds active against gram-positive and gram-negative bacteria

Abstract

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 of previous works, N-benzenesulfonyl-1,2,3,4-tetrahydroquinoline (BSTHQ) derivatives were described as antimicrobial agents active against gram-positive and gram-negative pathogens. In this work, experimental and molecular modelling studies were performed in order to identify their potential biological target in the light of structure-based design efforts towards further BSTHQ derivatives. First, a carboxyfluorescein leakage assay was performed using liposomes to mimic bacterial membranes, which found no significative membrane disruption effects with respect to control samples. These results support a non-surfactant antimicrobial activity of the tested compounds. In a second stage, the inhibition of potential antimicrobial targets was screened using molecular modelling methods, taking into account previously reported druggable targets deposited in the ChEMBL database for Escherichia coli and Staphylococcus aureus. Two enzymes, namely D-glutamic acid-adding enzyme (MurD) and N-acetylglucosamine-1-phophate-uridyltransferase (GlmU), both involved in bacterial membrane synthesis, were identified as potential targets. Pharmacodynamic interaction models were developed using known MurD and GlmU inhibitors by applying state-of-the-art chemoinformatic methods (molecular docking, molecular dynamics and free energy of interaction analyses). These models were further extended to the analysis of the studied BSTHQ derivatives. Overall, our results demonstrated that the studied BSTHQ derivatives elicit their antibacterial activity by interacting with a specific molecular target, GlmU being the highly feasible one. Based on the presented results, further structure-aided design efforts towards the obtaining of novel BSTHQ derivatives are envisioned.

Communicated by Ramaswamy H. Sarma

Keywords:

• BSTHQ derivatives
• potential biological target
• carboxyfluorescein leakage assay
• virtual screening
• Tanimoto similarity coefficients
• molecular docking
• molecular dynamic simulations
• GlmU

Acknowledgements

The authors would like to thank the CCAD (http://ccad.unc.edu.ar/), Universidad Nacional de Córdoba, Argentina, for providing access to computing resources. Mario A. Quevedo wishes to thank OpenEye Scientific Software and their Free Academic Licensing for providing licences to use the corresponding software packages.

Disclosure statement

There are no conflicts of interests to declare.

Additional information

Funding

Sergio R. Ribone and Mario A. Quevedo gratefully acknowledge the support of NVIDIA Corporation for the donation of a TitanXp GPU used in this research. This work was supported by the Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC); Fondo para la Investigación Científica y Tecnológica (FONCyT) under Grant number 2014-821 and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).