Synergistic interactions in two-drug and three-drug combinations (thymol,EDTA and vancomycin) against multi drug resistant bacteria including E. coli |
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| Institution: | 1. Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364 Heidelberg, Germany;2. Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University, Heidelberg, Germany;1. Medical Mycology Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, India;2. Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India;3. Department of Pharmaceutical Sciences, Tshwane University of Technology, Arcadia Campus, Pretoria 0001, South Africa;1. College of Food Science and Engineering, Northwest A&F University, Yangling, Shaanxi, 712100, China;2. Laboratory of Quality & Safety Risk Assessment for Agro-products (YangLing), Ministry of Agriculture, Yangling, Shaanxi, 712100, China;3. National Engineering Research Center of Agriculture Integration Test (Yangling), Yangling, Shaanxi, 712100, China;1. Laboratório de Pesquisa em Produtos Naturais, Universidade Regional do Cariri, Departamento de Química Biológica, 63105-000 Crato, CE, Brazil;2. Laboratório de Farmacologia e Química Molecular, Universidade Regional do Cariri, Departamento de Química Biológica, 63105-000 Crato, CE, Brazil;3. Laboratório de Microbiologia e Biologia Molecular, Universidade Regional do Cariri, Departamento de Química Biológica, 63105-000 Crato, CE, Brazil;1. Centre of Excellence for Pharmaceutical Sciences (PHARMACEN), North-West University, Potchefstroom, 2520, South Africa;2. Laboratory for Electron Microscopy, Chemical Resources Beneficiation Group, North-West University, Potchefstroom, 2520, South Africa;3. Unit for Environmental Sciences and Management, North-West University, Potchefstroom, 2520, South Africa;1. Laboratory of Analysis, Treatment and Valorization of Pollutants of the Environment and Products, Faculty of Pharmacy, Rue Avicenne, Monastir University, Tunisia;2. College of Applied Medical Sciences, Medical Laboratory Department, Yanbu el Bahr, Taibah University, Al Madinah Al Monawarah, Saudi Arabia;3. Laboratory of Bacteriology and Molecular Biology, Hôspital of Ibn El Jazzar, Kairouan, Tunisia;4. College of Sciences, Biology Department, Yanbu el Bahr, Taibah University, Al Madinah Al Monawarah, Kingdom Saudi Arabia |
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| Abstract: | Combinations of two or more drugs, which affect different targets, have frequently been used as a new approach against resistant bacteria. In our work we studied the antimicrobial activity (MIC, MBC) of individual drugs (the phenolic monoterpene thymol, EDTA and vancomycin), of two-drug interactions between thymol and EDTA in comparison with three-drug interactions with vancomycin against sensitive and resistant bacteria. Thymol demonstrated moderate bactericidal activity (MBC between 60 and 4000 μg/ml) while EDTA only exhibited bacteriostatic activity over a range of 60–4000 μg/ml. MICs of vancomycin were between 0.125 and 16 μg/ml against Gram-positive and between 32 and 128 μg/ml against Gram-negative bacteria. Checkerboard dilution and time-kill curve assays were performed to evaluate the mode of interaction of several combinations against Methicillin-resistant Staphylococcus aureus (MRSA NCTC 10442) and Escherichia coli (ATCC 25922). Checkerboard data indicate indifferent interaction against Gram-positive (FICI = 1–1.3) and synergy against Gram-negative bacteria (FICI ≈ 0.4), while time kill analyses suggest synergistic effect in different combinations against both types of bacteria. It is remarkable that the combinations could enhance the sensitivity of E. coli to vancomycin 16-fold to which it is normally insensitive. We have provided proof for the concept, that combinations of known antibiotics with modern phytotherapeutics can expand the spectrum of useful therapeutics. |
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| Keywords: | Thymol EDTA Vancomycin Multidrug resistance Two-drug interactions Three-drug interactions Synergy |
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