Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete with or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts acted as reservoirs for the accumulation of drug resistance during drug treatment. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure in the immunocompromised host was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of antibiotic. Therefore, antibiotic persistence mutations present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the emergence of high-level AMR.

鲍曼不动杆菌在医疗机构中越来越难以接受抗生素治疗。与大多数人类病原体一样，人们对抗菌素耐药性 (AMR) 的遗传途径以及免疫系统在疾病期间调节 AMR 中所起的作用知之甚少。在这里，我们重现了氟喹诺酮耐药的几种途径，在充满或耗尽中性粒细胞的小鼠中使用连续肺部感染进行进化实验，为耐药性的进化提供了两个关键见解。首先，中性粒细胞减少的宿主在药物治疗过程中充当了耐药性积累的储存库。在没有中性粒细胞的情况下，很容易选择具有改变的药物敏感性特征的变体，而具有免疫能力的动物会限制这些变体的出现。第二，免疫受损宿主的抗生素治疗失败显示在没有临床定义的耐药性的情况下发生，这是一个意想不到的结果，为在没有 AMR 的情况下临床上如何发生抗生素失败提供了一个模型。这两个结果背后的遗传机制是由激活药物出口泵调节器 AdeL 的突变启动的，它在抗生素存在的情况下驱动持久性。因此，抗生素持久性突变在疾病期间存在两方面的风险，导致免疫功能低下宿主的药物治疗失败，同时增加高水平 AMR 的出现。这两个结果背后的遗传机制是由激活药物出口泵调节器 AdeL 的突变启动的，它在抗生素存在的情况下驱动持久性。因此，抗生素持久性突变在疾病期间存在两方面的风险，导致免疫功能低下宿主的药物治疗失败，同时增加高水平 AMR 的出现。这两个结果背后的遗传机制是由激活药物出口泵调节器 AdeL 的突变启动的，它在抗生素存在的情况下驱动持久性。因此，抗生素持久性突变在疾病期间存在两方面的风险，导致免疫功能低下宿主的药物治疗失败，同时增加高水平 AMR 的出现。