Department of Biosciences, Rice Universitygrid.21940.3e, Houston, Texas, USA.
Center for Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
Antimicrob Agents Chemother. 2022 Jun 21;66(6):e0233321. doi: 10.1128/aac.02333-21. Epub 2022 May 11.
Infections caused by vancomycin-resistant Enterococcus faecium (VREfm) are an important public health threat. VREfm isolates have become increasingly resistant to the front-line antibiotic daptomycin (DAP). As such, the use of DAP combination therapies with other antibiotics like fosfomycin (FOS) has received increased attention. Antibiotic combinations could extend the efficacy of currently available antibiotics and potentially delay the onset of further resistance. We investigated the potential for E. faecium HOU503, a clinical VREfm isolate that is DAP and FOS susceptible, to develop resistance to a DAP-FOS combination. Of particular interest was whether the genetic drivers for DAP-FOS resistance might be epistatic and, thus, potentially decrease the efficacy of a combinatorial approach in either inhibiting VREfm or in delaying the onset of resistance. We show that resistance to DAP-FOS could be achieved by independent mutations to proteins responsible for cell wall synthesis for FOS and in altering membrane dynamics for DAP. However, we did not observe genetic drivers that exhibited substantial cross-drug epistasis that could undermine the DAP-FOS combination. Of interest was that FOS resistance in HOU503 was largely mediated by changes in phosphoenolpyruvate (PEP) flux as a result of mutations in pyruvate kinase (). Increasing PEP flux could be a readily accessible mechanism for FOS resistance in many pathogens. Importantly, we show that HOU503 was able to develop DAP resistance through a variety of biochemical mechanisms and was able to employ different adaptive strategies. Finally, we showed that the addition of FOS can prolong the efficacy of DAP and slow down DAP resistance .
万古霉素耐药粪肠球菌（VREfm）引起的感染是一个重要的公共卫生威胁。VREfm 分离株对一线抗生素达托霉素（DAP）的耐药性越来越强。因此，人们越来越关注 DAP 与其他抗生素如磷霉素（FOS）联合治疗的应用。抗生素联合使用可以延长现有抗生素的疗效，并可能延迟进一步耐药的发生。我们研究了对 DAP 和 FOS 敏感的临床 VREfm 分离株 HOU503 是否有可能对 DAP-FOS 联合用药产生耐药性。特别感兴趣的是，DAP-FOS 耐药的遗传驱动因素是否为上位性，从而可能降低联合用药抑制 VREfm 或延迟耐药发生的效果。我们发现，通过对 FOS 负责细胞壁合成的蛋白和改变 DAP 膜动力学的独立突变，可以实现对 DAP-FOS 的耐药性。然而，我们没有观察到表现出显著交叉药物上位性的遗传驱动因素，这可能会破坏 DAP-FOS 联合用药。有趣的是，HOU503 中的 FOS 耐药性主要是由于磷酸烯醇丙酮酸（PEP）通量的变化引起的，这是由于丙酮酸激酶（）突变所致。增加 PEP 通量可能是许多病原体产生 FOS 耐药性的一种易于获得的机制。重要的是，我们表明 HOU503 能够通过多种生化机制获得 DAP 耐药性，并能够采用不同的适应策略。最后，我们表明添加 FOS 可以延长 DAP 的疗效并减缓 DAP 耐药性的发展。
