Exposure of Methicillin-Resistant Staphylococcus aureus to Low Levels of the Antibacterial THAM-3ΦG Generates a Small Colony Drug-Resistant Phenotype.
Exposure of Methicillin-Resistant Staphylococcus aureus to Low Levels of the Antibacterial THAM-3ΦG Generates a Small Colony Drug-Resistant Phenotype.
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将耐甲氧西林金黄色葡萄球菌暴露于低水平的抗菌 THAM-3μG 会产生小菌落耐药表型。
DOI：
10.1038/s41598-018-28283-3
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发表时间：
2018
影响因子：
4.6
通讯作者：
Teintze,Martin
中科院分区：
文献类型：
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作者：
Weaver,AlanJ;Peters,TamiR;Tripet,Brian;VanVuren,Abigail;Rakesh;Lee,RichardE;Copié,Valérie;Teintze,Martin
本文研究了金黄色葡萄球菌对新型抗菌化合物三苯胍（THAM-3ΦG）的耐药性。通过培养甲氧西林抗性株来检测抗性发展。金黄色葡萄球菌（MRSA）与亚致死剂量的THAM-3ΦG.这很快导致S的正常（WT）和小集落（SC）的形成。金黄色葡萄球菌的最小抑菌浓度（MIC）比原始MIC高2倍和4倍。用增加浓度的THAM-3ΦG连续细胞传代导致MIC >64 mg/L的排他SC表型。基于核磁共振（NMR）的代谢组学和多变量统计分析揭示了THAM-3ΦG处理的WT、未处理的WT和SC（处理的和未处理的两者）的三种不同的代谢谱。SC样品组的代谢组模式与S的其他小菌落变体（SCV）报告的代谢组模式相匹配。金黄色。用甲萘醌补充SCV导致生长率几乎完全恢复。通过NMR分析证实了这种营养缺陷型，揭示了SCV中不存在甲基萘醌生产。总之，MRSA通过选择生长缓慢的甲萘醌营养缺陷型菌快速获得对THAM-3ΦG的抗性。这项研究强调了在开发过程中评估和监测新型抗菌药物耐药性的重要性。
This study investigated resistance against trishexylaminomelamine trisphenylguanide (THAM-3ΦG), a novel antibacterial compound with selective microbicidal activity againstStaphylococcus aureus. Resistance development was examined by culturing methicillin resistantS. aureus(MRSA) with sub-lethal doses of THAM-3ΦG. This quickly resulted in the formation of normal (WT) and small colonies (SC) ofS. aureusexhibiting minimal inhibitory concentrations (MICs) 2× and 4× greater than the original MIC. Continuous cell passaging with increasing concentrations of THAM-3ΦG 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-3ΦG 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) ofS. 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-3ΦG through selection of a slow-growing menaquinone auxotroph. This study highlights the importance of evaluating and monitoring resistance to novel antibacterials during development.