Functional profiling of CHAP domain-containing peptidoglycan hydrolases of Staphylococcus aureus USA300 uncovers potential targets for anti-staphylococcal therapies

IF 4.5 3区 医学 Q1 MICROBIOLOGY
Min Wang , Xiaofang Li , Francis M. Cavallo , Harita Yedavally , Sjouke Piersma , Elisa J.M. Raineri , Elias Vera Murguia , Jeroen Kuipers , Zhenhua Zhang , Jan Maarten van Dijl , Girbe Buist
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引用次数: 0

Abstract

The bacterial pathogen Staphylococcus aureus employs a thick cell wall for protection against physical and chemical insults. This wall requires continuous maintenance to ensure strength and barrier integrity, but also to permit bacterial growth and division. The main cell wall component is peptidoglycan. Accordingly, the bacteria produce so-called peptidoglycan hydrolases (PGHs) that cleave glycan strands to facilitate growth, cell wall remodelling, separation of divided cells and release of exported proteins into the extracellular milieu. A special class of PGHs contains so-called ‘cysteine, histidine-dependent amidohydrolase/peptidase’ (CHAP) domains. In the present study, we profiled the roles of 11 CHAP PGHs encoded by the core genome of S. aureus USA300 LAC. Mutant strains lacking individual CHAP PGHs were analysed for growth, cell morphology, autolysis, and invasion and replication inside human lung epithelial cells. The results show that several investigated CHAP PGHs contribute to different extents to extracellular and intracellular growth and replication of S. aureus, septation of dividing cells, daughter cell separation once the division process is completed, autolysis and biofilm formation. In particular, the CHAP PGHs Sle1 and SAUSA300_2253 control intracellular staphylococcal replication and the resistance to β-lactam antibiotics like oxacillin. This makes the S. aureus PGHs in general, and the Sle1 and SAUSA300_2253 proteins in particular, attractive targets for future prophylactic or therapeutic anti-staphylococcal interventions. Alternatively, these cell surface-exposed enzymes, or particular domains of these enzymes, could be applied in innovative anti-staphylococcal therapies.

金黄色葡萄球菌 USA300 含 CHAP 结构域肽聚糖水解酶的功能分析发现了抗葡萄球菌疗法的潜在靶点
细菌病原体金黄色葡萄球菌具有厚厚的细胞壁,可以抵御物理和化学侵袭。这种细胞壁需要持续维护,以确保强度和屏障完整性,同时也允许细菌生长和分裂。细胞壁的主要成分是肽聚糖。因此,细菌会产生所谓的肽聚糖水解酶(PGHs),它能裂解糖链,促进生长、细胞壁重塑、分裂细胞分离以及向细胞外环境释放输出蛋白质。一类特殊的 PGH 含有所谓的 "半胱氨酸、组氨酸依赖性酰胺水解酶/肽酶"(CHAP)结构域。在本研究中,我们分析了金黄色葡萄球菌 USA300 LAC 核心基因组编码的 11 个 CHAP PGH 的作用。我们对缺乏单个 CHAP PGHs 的突变菌株的生长、细胞形态、自溶以及在人肺上皮细胞内的侵袭和复制进行了分析。结果表明,所研究的几种CHAP PGH在不同程度上促进了金黄色葡萄球菌的胞外和胞内生长与复制、分裂细胞的隔膜、分裂过程完成后子细胞的分离、自溶和生物膜的形成。特别是,CHAP PGHs Sle1 和 SAUSA300_2253 可控制金黄色葡萄球菌的胞内复制和对β-内酰胺类抗生素(如奥沙西林)的耐药性。这使得金黄色葡萄球菌 PGHs,尤其是 Sle1 和 SAUSA300_2253 蛋白质,成为未来预防或治疗抗葡萄球菌干预措施的诱人靶标。另外,这些暴露于细胞表面的酶或这些酶的特定结构域也可用于创新的抗葡萄球菌疗法。
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来源期刊
CiteScore
9.70
自引率
0.00%
发文量
18
审稿时长
45 days
期刊介绍: Pathogen genome sequencing projects have provided a wealth of data that need to be set in context to pathogenicity and the outcome of infections. In addition, the interplay between a pathogen and its host cell has become increasingly important to understand and interfere with diseases caused by microbial pathogens. IJMM meets these needs by focussing on genome and proteome analyses, studies dealing with the molecular mechanisms of pathogenicity and the evolution of pathogenic agents, the interactions between pathogens and host cells ("cellular microbiology"), and molecular epidemiology. To help the reader keeping up with the rapidly evolving new findings in the field of medical microbiology, IJMM publishes original articles, case studies and topical, state-of-the-art mini-reviews in a well balanced fashion. All articles are strictly peer-reviewed. Important topics are reinforced by 2 special issues per year dedicated to a particular theme. Finally, at irregular intervals, current opinions on recent or future developments in medical microbiology are presented in an editorial section.
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