Structure-activity relationships of pyrazole-4-carbodithioates as antibacterials against methicillin–resistant Staphylococcus aureus |
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Authors: | Hiwa Majed Tatiana Johnston Celine Kelso Enrico Monachino Slobodan Jergic Nicholas E Dixon Eleftherios Mylonakis Michael J Kelso |
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Institution: | 1. School of Chemistry, University of Wollongong, and Illawarra Health and Medical Research Institute, Wollongong, New South Wales 2522, Australia;2. Department of Infectious Disease, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA |
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Abstract: | Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious hospital-acquired infections and is responsible for significant morbidity and mortality in residential care facilities. New agents against MRSA are needed to combat rising resistance to current antibiotics. We recently reported 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) as a new bacteriostatic agent against MRSA that appears to act via a novel mechanism. Here, twenty nine analogs of HMPC were synthesized, their anti-MRSA structure-activity relationships evaluated and selectivity versus human HKC-8 cells determined. Minimum inhibitory concentrations (MIC) ranged from 0.5 to 64?μg/mL and up to 16-fold selectivity was achieved. The 4-carbodithioate function was found to be essential for activity but non-specific reactivity was ruled out as a contributor to antibacterial action. The study supports further work aimed at elucidating the molecular targets of this interesting new class of anti-MRSA agents. |
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Keywords: | Antibacterial MRSA Pyrazole-4-carbodithioate MgrA |
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