Noto Michael J, Burns William J, Beavers William N, Skaar Eric P
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
J Bacteriol. 2017 Aug 8;199(17). doi: 10.1128/JB.00221-17. Print 2017 Sep 1.
and are commonly isolated from polymicrobial infections, such as wound infections and chronic respiratory infections of persons with cystic fibrosis. Despite their coisolation, produces substances toxic to , including pyocyanin, a blue-pigmented molecule that functions in virulence. Pyocyanin inhibits respiration, forcing it to derive energy from fermentation and adopt a small-colony variant (SCV) phenotype. The mechanisms by which sustains infection in the presence of pyocyanin are not clear. We sought to clarify the mechanisms of pyocyanin toxicity in as well as identify the staphylococcal factors involved in its resistance to pyocyanin toxicity. Nonrespiring SCVs are inhibited by pyocyanin through pyocyanin-dependent reactive oxygen species (ROS) production, indicating that pyocyanin toxicity is mediated through respiratory inhibition and ROS generation. Selection on pyocyanin yielded a menadione auxotrophic SCV capable of growth on high concentrations of pyocyanin. Genome sequencing of this isolate identified mutations in four genes, including , , NWMN_0006, and QsrR is a quinone-sensing repressor of quinone detoxification genes. Inactivation of resulted in significant pyocyanin resistance, and additional pyocyanin resistance was achieved through combined inactivation of and menadione biosynthesis. Pyocyanin-resistant has an enhanced capability to inactivate pyocyanin, suggesting QsrR-regulated gene products may degrade pyocyanin to alleviate toxicity. These findings demonstrate pyocyanin-mediated ROS generation as an additional mechanism of pyocyanin toxicity and define QsrR as a key mediator of pyocyanin resistance in Many bacterial infections occur in the presence of other microbes, where interactions between different microbes and the host impact disease. In patients with cystic fibrosis, chronic lung infection with multiple microbes results in the most severe disease manifestations. and are prevalent cystic fibrosis pathogens, and infection with both is associated with worse outcomes. These organisms have evolved mechanisms of competing with one another. For example, produces pyocyanin, which inhibits growth. Our research has identified how pyocyanin inhibits growth and how can adapt to survive in the presence of pyocyanin. Understanding how sustains infection in the presence of may identify means of disrupting these microbial communities.
[具体细菌名称1]和[具体细菌名称2]通常从多种微生物感染中分离出来，如伤口感染和囊性纤维化患者的慢性呼吸道感染。尽管它们常常共同被分离出来，但[具体细菌名称1]会产生对[具体细菌名称2]有毒的物质，包括绿脓菌素，一种在[具体细菌名称1]毒力方面起作用的蓝色色素分子。绿脓菌素会抑制[具体细菌名称2]的呼吸作用，迫使它从发酵中获取能量并呈现小菌落变体（SCV）表型。在绿脓菌素存在的情况下，[具体细菌名称2]维持感染的机制尚不清楚。我们试图阐明绿脓菌素对[具体细菌名称2]的毒性机制，并确定葡萄球菌中参与其对绿脓菌素毒性抗性的因素。不进行呼吸作用的[具体细菌名称2]SCV会被绿脓菌素通过依赖绿脓菌素的活性氧（ROS）产生而抑制，这表明绿脓菌素毒性是通过呼吸抑制和ROS生成介导的。在绿脓菌素上进行筛选得到了一种能够在高浓度绿脓菌素上生长的甲萘醌营养缺陷型SCV。对该分离株进行基因组测序发现四个基因发生了突变，包括[具体基因名称1]、[具体基因名称2]、NWMN_0006和[具体基因名称3]。QsrR是醌解毒基因的醌感应阻遏物。[具体基因名称1]的失活导致对绿脓菌素的显著抗性，通过[具体基因名称2]和甲萘醌生物合成的联合失活实现了额外的绿脓菌素抗性。对绿脓菌素具有抗性的[具体细菌名称2]具有增强的绿脓菌素失活能力，这表明QsrR调控的基因产物可能降解绿脓菌素以减轻毒性。这些发现证明了绿脓菌素介导的ROS生成是绿脓菌素毒性的另一种机制，并将QsrR定义为[具体细菌名称2]中绿脓菌素抗性的关键介质。许多细菌感染发生在存在其他微生物的情况下，不同微生物与宿主之间的相互作用会影响疾病。在囊性纤维化患者中，多种微生物的慢性肺部感染会导致最严重的疾病表现。[具体细菌名称1]和[具体细菌名称2]是常见的囊性纤维化病原体，两者同时感染与更差的预后相关。这些生物体已经进化出相互竞争的机制。例如，[具体细菌名称1]产生绿脓菌素，它会抑制[具体细菌名称2]的生长。我们的研究已经确定了绿脓菌素如何抑制[具体细菌名称2]的生长以及[具体细菌名称2]如何在绿脓菌素存在的情况下适应生存。了解[具体细菌名称2]在[具体细菌名称1]存在的情况下如何维持感染可能会找到破坏这些微生物群落的方法。
