Zhang Liyang, Xu Qi, Tan Filemon C, Deng Yanhan, Hakki Morgan, Shelburne Samuel A, Kirienko Natalia V
Department of BioSciences, Rice University, Houston, TX, United States.
Department of Bioengineering, Rice University, Houston, TX, United States.
bioRxiv. 2024 Oct 7:2024.10.07.616987. doi: 10.1101/2024.10.07.616987.
Infections with antimicrobial resistant pathogens, such as are a frequent occurrence in healthcare settings. Human infections are predominantly caused by a small number of sequence types (ST), such as ST235, ST111, and ST175. Although ST111 is recognized as one of the most prevalent high-risk clones worldwide and frequently exhibits multidrug-resistant or extensively drug-resistant phenotypes, the basis for this dominance remains unclear. In this study, we used a genome-wide transposon insertion library screen to discover that the competitive advantage of ST111 strains over certain non-ST111 strains is through production of R pyocins. We confirmed this finding by showing that competitive dominance was lost by ST111 mutants with R pyocin gene deletions. Further investigation showed that sensitivity to ST111 R pyocin (specifically R5 pyocin) is caused by deficiency in the O-antigen ligase , which leaves lipopolysaccharide (LPS) bereft of O antigen, enabling pyocins to bind the LPS core. In contrast, sensitivity of mutants to R1 or R2 pyocins depended on additional genomic changes. In addition, we found the PA14 mutants in lipopolysaccharide biosynthesis (, , ) that cause high susceptibility to R pyocins also exhibit poor swimming motility. Analysis of 5,135 typed strains revealed that several international, high-risk sequence types (including ST235, ST111, and ST175) are enriched for R5 pyocin production, indicating a correlation between these phenotypes and suggesting a novel approach for evaluating risk from emerging prevalent strains. Overall, our study sheds light on the mechanisms underlying the dominance of ST111 strains and highlighting the role of in extending spectrum of R pyocin susceptibility.
耐抗菌性病原体感染，如在医疗机构中经常发生。人类感染主要由少数序列类型（ST）引起，如ST235、ST111和ST175。尽管ST111被认为是全球最普遍的高风险克隆之一，并且经常表现出多重耐药或广泛耐药表型，但其这种优势的基础仍不清楚。在本研究中，我们使用全基因组转座子插入文库筛选发现，ST111菌株相对于某些非ST111菌株的竞争优势是通过产生R型绿脓菌素。我们通过表明具有R型绿脓菌素基因缺失的ST111突变体失去竞争优势来证实了这一发现。进一步研究表明，对ST111 R型绿脓菌素（特别是R5绿脓菌素）的敏感性是由O抗原连接酶缺陷引起的，这使得脂多糖（LPS）缺乏O抗原，从而使绿脓菌素能够结合LPS核心。相比之下，突变体对R1或R2绿脓菌素的敏感性取决于额外的基因组变化。此外，我们发现脂多糖生物合成中的PA14突变体（、、）对R型绿脓菌素高度敏感，同时也表现出较差的游动能力。对5135株分型菌株的分析表明，几种国际高风险序列类型（包括ST235、ST111和ST175）富含R5绿脓菌素的产生，表明这些表型之间存在相关性，并提示了一种评估新兴流行菌株风险的新方法。总体而言，我们的研究揭示了ST111菌株优势的潜在机制，并突出了在扩展R型绿脓菌素敏感性谱中的作用。
