Vaillancourt Mylene, Limsuwannarot Sam P, Bresee Catherine, Poopalarajah Rahgavi, Jorth Peter
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Biostatistics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Antibiotics (Basel). 2021 Sep 25;10(10):1164. doi: 10.3390/antibiotics10101164.
Antibiotic-resistant infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in that increased expression of the efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for , increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.
抗生素耐药性感染是囊性纤维化（CF）患者死亡的主要原因。然而，直到最近人们才认识到，即使在没有抗生素的情况下，耐药性突变也会增加毒力。此外，耐药性突变增加毒力的机制还知之甚少。在本研究中，我们检验了影响外排泵的突变可直接增加毒力这一假设。通过遗传学、生理学分析和模型感染，我们发现外排泵突变可增加毒力。外排泵系统的突变在小鼠感染模型中增加了群体运动、鼠李糖脂的产生和致死率，而增加外排系统表达的突变在急性小鼠肺部感染期间增加了毒力，同时不影响群体运动或鼠李糖脂基因表达。最后，我们发现一种外排泵抑制剂（这是一种针对[此处原文缺失相关内容]提出的新型治疗方法）以剂量依赖的方式增加了鼠李糖脂基因的表达。这一发现很重要，因为鼠李糖脂是参与通过上皮屏障扩散并导致中性粒细胞坏死的关键毒力因子。总之，这些数据表明，目前和未来拟用的抗铜绿假单胞菌治疗方法可能会因增加毒力而无意中使感染恶化。因此，针对外排泵的治疗应谨慎进行。
