Radlinski Lauren, Rowe Sarah E, Kartchner Laurel B, Maile Robert, Cairns Bruce A, Vitko Nicholas P, Gode Cindy J, Lachiewicz Anne M, Wolfgang Matthew C, Conlon Brian P
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, North Carolina, United States of America.
North Carolina Jaycee Burn Center, University of North Carolina at Chapel Hill, North Carolina, United States of America.
PLoS Biol. 2017 Nov 27;15(11):e2003981. doi: 10.1371/journal.pbio.2003981. eCollection 2017 Nov.
Chronic coinfections of Staphylococcus aureus and Pseudomonas aeruginosa frequently fail to respond to antibiotic treatment, leading to significant patient morbidity and mortality. Currently, the impact of interspecies interaction on S. aureus antibiotic susceptibility remains poorly understood. In this study, we utilize a panel of P. aeruginosa burn wound and cystic fibrosis (CF) lung isolates to demonstrate that P. aeruginosa alters S. aureus susceptibility to bactericidal antibiotics in a variable, strain-dependent manner and further identify 3 independent interactions responsible for antagonizing or potentiating antibiotic activity against S. aureus. We find that P. aeruginosa LasA endopeptidase potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent tobramycin uptake, and 2-heptyl-4-hydroxyquinoline N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We find that the production of each of these factors varies between clinical isolates and corresponds to the capacity of each isolate to alter S. aureus antibiotic susceptibility. Furthermore, we demonstrate that vancomycin treatment of a S. aureus mouse burn infection is potentiated by the presence of a LasA-producing P. aeruginosa population. These findings demonstrate that antibiotic susceptibility is complex and dependent not only upon the genotype of the pathogen being targeted, but also on interactions with other microorganisms in the infection environment. Consideration of these interactions will improve the treatment of polymicrobial infections.
金黄色葡萄球菌和铜绿假单胞菌的慢性合并感染对抗生素治疗常常无反应，导致患者出现显著的发病和死亡情况。目前，种间相互作用对金黄色葡萄球菌抗生素敏感性的影响仍知之甚少。在本研究中，我们利用一组来自烧伤创面和囊性纤维化（CF）肺部的铜绿假单胞菌分离株，证明铜绿假单胞菌以可变的、菌株依赖性方式改变金黄色葡萄球菌对杀菌抗生素的敏感性，并进一步确定了3种独立的相互作用，这些相互作用可拮抗或增强针对金黄色葡萄球菌的抗生素活性。我们发现，铜绿假单胞菌的LasA内肽酶可增强万古霉素对金黄色葡萄球菌的裂解作用，鼠李糖脂有助于不依赖质子动力的妥布霉素摄取，2-庚基-4-羟基喹啉N-氧化物（HQNO）通过抑制呼吸和降低细胞ATP水平诱导金黄色葡萄球菌产生多药耐受性。我们发现，这些因子在临床分离株中的产生情况各不相同，且与每个分离株改变金黄色葡萄球菌抗生素敏感性的能力相对应。此外，我们证明，存在产生LasA的铜绿假单胞菌群体可增强万古霉素对金黄色葡萄球菌小鼠烧伤感染的治疗效果。这些发现表明，抗生素敏感性很复杂，不仅取决于被靶向病原体的基因型，还取决于与感染环境中其他微生物的相互作用。考虑这些相互作用将改善对混合微生物感染的治疗。
