Precise spatial structure impacts antimicrobial susceptibility of S. aureus in polymicrobial wound infections.
Precise spatial structure impacts antimicrobial susceptibility of S. aureus in polymicrobial wound infections.
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DOI：
10.1073/pnas.2212340119
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发表时间：
2022-12-20
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
对感染期间微生物相互作用的理解通常缺乏生物地理背景，限制了对群落功能的理解。使用小鼠慢性伤口模型，我们在宏观和微观尺度上表征了铜绿假单胞菌和金黄色葡萄球菌单感染和混合感染的空间结构。我们发现这些细菌在慢性伤口中以高密度共存，呈现出斑片状分布。此外，我们量化了精确的空间结构，发现与细菌负荷不同，空间结构由伤口内的位置决定，并依赖于铜绿假单胞菌分泌的抗菌剂。重要的是，空间结构的破坏改变了金黄色葡萄球菌的抗生素耐受性。这项工作强调了微生物相互作用对于建立多种微生物感染的空间结构的重要性，并暗示生物地理学是抗菌功效的关键决定因素。微生物生态学的一个标志是群落成员之间的相互作用塑造群落功能。这包括人类感染中的微生物群落，例如慢性伤口，其中的相互作用可能导致更严重的疾病。金黄色葡萄球菌是从人类慢性伤口感染中分离出的最常见的微生物，并且已被证明与铜绿假单胞菌具有合作和竞争相互作用。尽管如此，尽管进行了大量研究，这些微生物之间的大多数相互作用仍然是使用体外充分混合的系统来表征的，该系统不能概括感染环境。在这里，我们描述了慢性小鼠伤口中金黄色葡萄球菌和铜绿假单胞菌之间的相互作用，重点关注宏观和微观空间结构在疾病中发挥的作用。我们发现金黄色葡萄球菌和铜绿假单胞菌在小鼠伤口中以高细胞密度共存。高分辨率成像显示，这些微生物呈斑片状分布，仅占伤口体积的 5% 至 25%。使用定量框架，我们在宏观 (mm) 和微观 (μm) 尺度上确定了精确的空间结构，这主要是由铜绿假单胞菌产生抗菌剂 2-庚基-4-羟基喹啉 N-氧化物介导的，而抗菌绿脓素则没有影响。最后，我们发现这种精确的空间结构增强了金黄色葡萄球菌对氨基糖苷类抗生素的耐受性，但不增强万古霉素的耐受性。我们的结果为金黄色葡萄球菌和铜绿假单胞菌共感染伤口的生物地理学提供了机制见解，并表明空间结构是伤口感染中抗菌药物耐受性的关键决定因素。
Understanding of microbial interactions during infection often lacks biogeographical context, limiting understanding of community function. Using a mouse chronic wound model, we characterized the spatial structure of P. aeruginosa and S. aureus mono- and co-infections at the macro- and micro-scales. We discovered these bacteria coexist at high densities in chronic wounds, exhibiting a patchy distribution. Further, we quantified a precise spatial structure and found unlike bacterial burdens, spatial structure was dictated by location within the wound and dependent on a P. aeruginosa-secreted antimicrobial. Importantly, disruptions to the spatial structure altered S. aureus antibiotic tolerance. This work highlights the importance of microbial interactions for establishing the spatial structure in polymicrobial infections and implicates biogeography as a key determinant of antimicrobial efficacy. A hallmark of microbial ecology is that interactions between members of a community shape community function. This includes microbial communities in human infections, such as chronic wounds, where interactions can result in more severe diseases. Staphylococcus aureus is the most common organism isolated from human chronic wound infections and has been shown to have both cooperative and competitive interactions with Pseudomonas aeruginosa. Still, despite considerable study, most interactions between these microbes have been characterized using in vitro well-mixed systems, which do not recapitulate the infection environment. Here, we characterized interactions between S. aureus and P. aeruginosa in chronic murine wounds, focusing on the role that both macro- and micro-scale spatial structures play in disease. We discovered that S. aureus and P. aeruginosa coexist at high cell densities in murine wounds. High-resolution imaging revealed that these microbes establish a patchy distribution, only occupying 5 to 25% of the wound volume. Using a quantitative framework, we identified a precise spatial structure at both the macro (mm)- and micro (µm)-scales, which was largely mediated by P. aeruginosa production of the antimicrobial 2-heptyl-4-hydroxyquinoline N-oxide, while the antimicrobial pyocyanin had no impact. Finally, we discovered that this precise spatial structure enhances S. aureus tolerance to aminoglycoside antibiotics but not vancomycin. Our results provide mechanistic insights into the biogeography of S. aureus and P. aeruginosa coinfected wounds and implicate spatial structure as a key determinant of antimicrobial tolerance in wound infections.
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影响因子：
3.7
作者：
Dalton T;Dowd SE;Wolcott RD;Sun Y;Watters C;Griswold JA;Rumbaugh KP
通讯作者：
Rumbaugh KP
影响因子：
3.7
作者：
Dowd SE;Wolcott RD;Sun Y;McKeehan T;Smith E;Rhoads D
通讯作者：
Rhoads D
影响因子：
3.6
作者：
Dietrich, Lars E. P.;Price-Whelan, Alexa;Newman, Dianne K.
通讯作者：
Newman, Dianne K.
影响因子：
6.4
作者：
Cigana, Cristina;Bianconi, Irene;Bragonzi, Alessandra
通讯作者：
Bragonzi, Alessandra
影响因子：
3.2
作者：
Filkins, Laura M.;Graber, Jyoti A.;O'Toole, George A.
通讯作者：
O'Toole, George A.