| Institution: | 1. Aix-Marseille Univ, CNRS, LISM, Institut de Microbiologie de la Méditerranée, Marseille, France;2. Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 8204 – CIIL – Center for Infection and Immunity of Lille, Lille, France;3. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France;4. Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille Protéomique, Marseille, France;1. Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar 388121, India;2. Chemistry Departments, V. P. and R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar 388120, India;1. Departmentof Chemistry, Quaid-i-Azam University-45320, Islamabad, Pakistan;2. University of Florence, NEUROFARBA Department, Pharmaceutical and Nutraceutical Sciences Section, via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Aix-Marseille Univ, CNRS, EIPL, Marseille, France;2. Aix-Marseille Univ, CNRS, Centrale Marseille, ISM2, France;3. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 – CNRS – UM – ENSCM, Faculté de Pharmacie, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France;4. ITERG-ENMS, Université de Bordeaux, rue Léo Saignat, 33076 Bordeaux Cedex, France;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey;2. Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan;3. Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey;4. Neurofarba Department, Sezione di Scienza Farmaceutiche e Nutraceutiche, Universita egli Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;1. Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Dadri, Uttar Pradesh 201314, India;2. Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, #3A2, Jupiter, FL 33458, USA;1. Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA;2. Bristol-Myers Squibb, Research and Development, PO Box 4000, Princeton, NJ 08540, USA |
| Abstract: | A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc26230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M. tb H37Rv growth either in broth medium or inside macrophages. The OX compounds displayed a diversity of action and were found to act either on extracellular M. tb growth only with moderated MIC50, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth. Of interest, all OX derivatives exhibited very low toxicity towards host macrophages. Among the six potential OXs identified, HPOX, a selective inhibitor of extracellular M. tb growth, was selected and further used in a competitive labelling/enrichment assay against the activity-based probe Desthiobiotin-FP, in order to identify its putative target(s). This approach, combined with mass spectrometry, identified 18 potential candidates, all being serine or cysteine enzymes involved in M. tb lipid metabolism and/or in cell wall biosynthesis. Among them, Ag85A, CaeA, TesA, KasA and MetA have been reported as essential for in vitro growth of M. tb and/or its survival and persistence inside macrophages. Overall, our findings support the assumption that OX derivatives may represent a novel class of multi-target inhibitors leading to the arrest of M. tb growth through a cumulative inhibition of a large number of Ser- and Cys-containing enzymes involved in various important physiological processes. |
