Exposure of Methicillin-Resistant Staphylococcus aureus to Low Levels of the Antibacterial THAM-3?G Generates a Small Colony Drug-Resistant Phenotype
Alan J. Weaver, Tami R. Peters, Brian Tripet, Abigail Van Vuren, Richard E. Lee Rakesh, Valerie Copie, Martin Teintze
This study investigated resistance against trishexylaminomelamine trisphenylguanide (THAM-3?G), a novel antibacterial compound with selective microbicidal activity against Staphylococcus aureus. Resistance development was examined by culturing methicillin resistant S. aureus (MRSA) with sub-lethal doses of THAM-3?G. This quickly resulted in the formation of normal (WT) and small colonies (SC) of S. aureus exhibiting minimal inhibitory concentrations (MICs) 2× and 4× greater than the original MIC. Continuous cell passaging with increasing concentrations of THAM-3?G resulted in an exclusively SC phenotype with MIC >64?mg/L. Nuclear magnetic resonance (NMR)-based metabolomics and multivariate statistical analysis revealed three distinct metabolic profiles for THAM-3?G treated WT, untreated WT, and SC (both treated and untreated). The metabolome patterns of the SC sample groups match those reported for other small colony variants (SCV) of S. aureus. Supplementation of the SCV with menadione resulted in almost complete recovery of growth rate. This auxotrophism was corroborated by NMR analysis revealing the absence of menaquinone production in the SCV. In conclusion, MRSA rapidly acquires resistance to THAM-3?G through selection of a slow-growing menaquinone auxotroph. This study highlights the importance of evaluating and monitoring resistance to novel antibacterials during development.
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