Building blocks and blueprints for bacterial autolysins.
Building blocks and blueprints for bacterial autolysins.
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细菌自溶素的构建模块和蓝图。
DOI：
10.1371/journal.pcbi.1008889
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发表时间：
2021-04
影响因子：
4.3
通讯作者：
Bailey-Kellogg C
中科院分区：
文献类型：
--
作者：
Mitchell SJ;Verma D;Griswold KE;Bailey-Kellogg C
细菌利用多种内源性细胞壁水解酶或自溶素在包括细胞分裂、生物膜形成和程序性死亡的过程中重塑它们的细胞壁。我们在这里系统地研究这些酶的组成，以深入了解其相关的生物过程，通过化疗破坏它们的潜在方法，以及它们可能被用作重组抗菌生物疗法的策略。为了做到这一点，我们开发了LEDALGORY（按生物体分组的裂解酶结构域），这是一种用于创建和分析自溶酶序列数据库、组成结构域注释以及整合肽聚糖结合和降解功能的多结构域酶的结构模式的管道。我们将LEDtron应用于8种致病菌，革兰氏阴性鲍曼不动杆菌、肺炎克雷伯菌、淋病奈瑟菌和铜绿假单胞菌;革兰氏阳性艰难梭菌、屎肠球菌、金黄色葡萄球菌和肺炎链球菌。这些病原体的自溶酶谱的分析揭示了它们的关键结构域构建块和架构的共性和差异，包括多结构域酶中结构域之间的相关性和优先顺序，具有潜在互补识别模式的同源结合结构域的重复，以及指示相关结构域之间功能特异性的潜在分歧的序列相似性模式。我们进一步确定了各种未注释的序列区域内的溶解酶，可能本身含有新的结构域具有重要的功能。细菌使用称为“自溶素”的酶来重塑它们的细胞壁，例如在细胞分裂和生物膜形成期间。我们已经开发了一个生物信息学管道来分析许多不同病原菌的自溶素库，比较和对比它们的自溶素构建的结构域构建块，结构域的氨基酸序列多样性，以及结构域组装成完整酶的结构模式。我们的分析提供了重要的生物过程的见解，表明可能从实验表征中受益的序列，突出了化疗干预的潜在目标，甚至提出了构建下一代自溶素生物疗法的策略，这些生物疗法可以使病原体自身的蛋白质对抗它，以破坏其细胞壁。
Bacteria utilize a wide variety of endogenous cell wall hydrolases, or autolysins, to remodel their cell walls during processes including cell division, biofilm formation, and programmed death. We here systematically investigate the composition of these enzymes in order to gain insights into their associated biological processes, potential ways to disrupt them via chemotherapeutics, and strategies by which they might be leveraged as recombinant antibacterial biotherapies. To do so, we developed LEDGOs (lytic enzyme domains grouped by organism), a pipeline to create and analyze databases of autolytic enzyme sequences, constituent domain annotations, and architectural patterns of multi-domain enzymes that integrate peptidoglycan binding and degrading functions. We applied LEDGOs to eight pathogenic bacteria, gram negatives Acinetobacter baumannii, Klebsiella pneumoniae, Neisseria gonorrhoeae, and Pseudomonas aeruginosa; and gram positives Clostridioides difficile, Enterococcus faecium, Staphylococcus aureus, and Streptococcus pneumoniae. Our analysis of the autolytic enzyme repertoires of these pathogens reveals commonalities and differences in their key domain building blocks and architectures, including correlations and preferred orders among domains in multi-domain enzymes, repetitions of homologous binding domains with potentially complementarity recognition modalities, and sequence similarity patterns indicative of potential divergence of functional specificity among related domains. We have further identified a variety of unannotated sequence regions within the lytic enzymes that may themselves contain new domains with important functions. Bacteria use enzymes called “autolysins” to remodel their cell walls, for example during cell division and formation of biofilms. We have developed a bioinformatics pipeline to analyze the autolysin repertoires of a number of different pathogenic bacteria, comparing and contrasting the domain building blocks from which their autolysins are constructed, the amino acid sequence diversity of the domains, and the architectural patterns by which the domains are assembled into complete enzymes. Our analysis provides insights into important biological processes, indicates sequences that would likely benefit from experimental characterization, highlights potential targets for chemotherapeutic intervention, and even suggests strategies for building next-generation autolysin biotherapies that turn a pathogen’s own proteins against it to destroy its cell wall.
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影响因子：
14.9
作者：
NCBI Resource Coordinators
通讯作者：
NCBI Resource Coordinators
影响因子：
16.1
作者：
Chen, Xiaoying;Zaro, Jennica L.;Shen, Wei-Chiang
通讯作者：
Shen, Wei-Chiang
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
3.7
作者：
Bose JL;Lehman MK;Fey PD;Bayles KW
通讯作者：
Bayles KW
影响因子：
13.6
作者：
Gerstmans, H.;Grimon, D.;Briers, Y.
通讯作者：
Briers, Y.