School of Pharmacy, University College London, London, United Kingdom.
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
mSphere. 2018 Nov 7;3(6):e00537-18. doi: 10.1128/mSphere.00537-18.
The capacity to resist the bactericidal action of complement (C') is a strong but poorly understood virulence trait in spp. Killing requires activation of one or more C' pathways, assembly of C5b-9 membrane attack complexes (MACs) on the surface of the outer membrane (OM), and penetration of MACs into the target bilayer. We interrogated whole-genome sequences of 164 isolates from three tertiary hospitals in Thailand for genes encoding surface-located macromolecules considered to play a role in determination of C' resistance. Most isolates (154/164) were identified as , and the collection conformed to previously established population structures and antibiotic resistance patterns. The distribution of sequence types (STs) and capsular (K) types were also typical of global populations. The majority (64%) of isolates were resistant to C', and the remainder were either rapidly or slowly killed. All isolates carried genes encoding capsular polysaccharides (K antigens), which have been strongly linked to C' resistance. In contrast to previous reports, there were no differences in the amount of capsule produced by C'-resistant isolates compared to C'-susceptible isolates, nor was there any correlation between serum reactivity and the presence of hypermucoviscous capsules. Similarly, there were no correlations between the presence of genes specifying lipopolysaccharide O-side chains or major OM proteins. Some virulence factors were found more frequently in C'-resistant isolates but were considered to reflect clonal ST expansion. Thus, no single gene accounts for the C' resistance of the isolates sequenced in this study. Multidrug-resistant is responsible for an increasing proportion of nosocomial infections, and emerging hypervirulent clones now cause severe community-acquired infections in otherwise healthy individuals. These bacteria are adept at circumventing immune defenses, and most survive and grow in serum; their capacity to avoid C'-mediated destruction is correlated with their invasive potential. Killing of Gram-negative bacteria occurs following activation of the C' cascades and stable deposition of C5b-9 MACs onto the OM. For , studies with mutants and conjugants have invoked capsules, lipopolysaccharide O-side chains, and OM proteins as determinants of C' resistance, although the precise roles of the macromolecules are unclear. In this study, we sequenced 164 isolates with different C' susceptibilities to identify genes involved in resistance. We conclude that no single OM constituent can account for resistance, which is likely to depend on biophysical properties of the target bilayer.
抵抗补体（C'）杀菌作用的能力是 spp. 的一个强大但理解甚少的毒力特征。杀伤需要激活一个或多个 C'途径，在外膜（OM）表面组装 C5b-9 膜攻击复合物（MAC），并将 MAC 穿透靶双层。我们对来自泰国三家三级医院的 164 株的全基因组序列进行了检测，以鉴定被认为在确定 C'抗性中起作用的表面定位大分子的编码基因。大多数分离株（154/164）被鉴定为 ，并且该集合符合先前建立的种群结构和抗生素耐药模式。序列型（ST）和荚膜（K）型的分布也与全球种群典型。大多数（64%）分离株对 C'有抗性，其余分离株则快速或缓慢死亡。所有分离株均携带编码荚膜多糖（K 抗原）的基因，这些基因与 C'抗性强烈相关。与先前的报告相反，C'抗性分离株与 C'敏感分离株相比，荚膜的产生量没有差异，血清反应性与高粘液荚膜的存在也没有相关性。同样，脂多糖 O-侧链或主要 OM 蛋白指定基因的存在也没有相关性。在 C'抗性分离株中发现了一些毒力因子，但被认为反映了克隆 ST 的扩张。因此，没有单个基因可以解释本研究中测序的分离株的 C'抗性。多药耐药 是医院获得性感染的比例不断增加的原因，而新兴的高毒力 克隆现在在其他健康个体中引起严重的社区获得性感染。这些细菌善于规避免疫防御，并且大多数在血清中存活和生长；它们避免 C'介导的破坏的能力与它们的侵袭潜力相关。革兰氏阴性细菌的杀伤发生在 C'级联的激活和 C5b-9 MAC 稳定沉积到 OM 之后。对于 ，突变体和接合子的研究已经将荚膜，脂多糖 O-侧链和 OM 蛋白作为 C'抗性的决定因素，尽管大分子的确切作用尚不清楚。在这项研究中，我们对具有不同 C'敏感性的 164 株进行了测序，以鉴定与抗性相关的基因。我们得出的结论是，没有单个 OM 成分可以解释抗性，这可能取决于靶双层的物理性质。
