Novel membrane remodeling systems in Actinobacteria and their role in antibiotic resistance

放线菌中的新型膜重塑系统及其在抗生素耐药性中的作用

• 批准号: 9888330
• 负责人: Herve Roy
• 金额: $ 18.63万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-06 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888330
• 关键词: Actinobacteria class; Actinomyces Infections; Affect; Amino Acids; Aminoacylation; Antibiotic Resistance; Antibiotics; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Bacteria; Bacterial Antibiotic Resistance; Bacterial Genome; Biochemical; Bioinformatics; Biological; Cations; Cell Wall; Cell membrane; Cell physiology; Cells; Charge; Chemicals; Corynebacterium; Corynebacterium pseudotuberculosis; Defense Mechanisms; Development; Diglycerides; Diphtheria; Environment; Enzymes; Etiology; Event; Exhibits; Exposure to; Firmicutes; Foundations; Future; Genus Mycobacterium; Goals; Head; Health; Homologous Gene; Human; Immune system; In Vitro; Individual; Infection; Innate Immune System; Insecta; Integral Membrane Protein; Investigation; Knock-out; Lead; Leprosy; Lipids; Lysine-Specific tRNA; Mass Spectrum Analysis; Mediating; Membrane; Membrane Lipids; Methods; Modeling; Modification; Mycobacterium abscessus; Nature; Nocardia; Nocardia Infections; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Permeability; Pharmaceutical Preparations; Phosphatidylglycerols; Physiological; Property; Protein Family; Proteins; Proteobacteria; Public Health; Resistance; Rhodococcus; Rhodococcus equi; Role; Specificity; Staphylococcus aureus; Streptomyces; Stress; System; Techniques; Testing; Transfer RNA; Tuberculosis; Ursidae Family; Variant; Virulence; Work; antimicrobial; antimicrobial drug; antimicrobial peptide; bacterial resistance; base; cell envelope; genome analysis; human pathogen; innovation; member; novel; pathogen; resistance factors; resistance mechanism

Bacterial resistance to antimicrobials is among the biggest challenges affecting human health. Many resistance mechanisms developed by bacteria involve adaptation of cell wall components that lead to decreased interaction with, or permeability to antimicrobial compounds. One such mechanism uses amino acids (aa), carried by tRNAs, to aminoacylate phosphatidylglycerol (PG), one of the main constituents of the bacterial membrane. Since the initial discovery of this pathway, studies have shown that lipid aminoacylation enzymes (more generally referred to as aminoacyl-phosphatidylglycerol synthases; aaPGSs) are surprisingly diverse, and have several aa in their repertoire for altering the chemical makeup of bacterial membranes. Numerous studies have demonstrated that PG aminoacylation enhances bacterial resistance to antibiotics that target the membrane (such as cationic antimicrobial peptides, CAMPs), as well as the virulence of pathogens from multiple phyla (i.e., Firmicutes and Proteobacteria). However, lipid modification systems have been largely ignored in the Actinobacteria, an important bacterial phylum that includes pathogens of major importance to human health, such as the etiological agents of tuberculosis, diphtheria, nocardiosis, and actinomycosis. An extensive genome analysis showed that bacteria in this phylum frequently harbor multiple (up to six) aaPGS homologs, suggesting that Actinobacteria display a high level of functional diversity in their lipid modification systems. Our preliminary studies validated this hypothesis, leading to discovery of several novel lipid modifications systems in corynebacteria that are important for antimicrobial resistance and virulence. A multitude of other lipid-modifying enzymes in Actinobacteria are yet to be described, and we hypothesize that some of these proteins support novel functions as well. These studies are important because aaPGSs represent general factors for membrane adaptation and are expressed in species of extreme importance to human health. Identification of novel lipid modifications will not only increase our understanding of fundamental bacterial defense mechanisms, but will reveal new targets for development of antimicrobial compounds. Our long-term goal is to define the repertoire of lipid modifications across bacterial species and to characterize their role in cellular physiology, antimicrobial resistance, and pathogenesis. The aims of this proposal, which will lay the groundwork for future studies, are to i) explore aaPGS homolog diversity in Actinobacteria and characterize the biochemical functions of representative enzymes from human pathogens in the genera Mycobacterium, Nocardia, Rhodococcus, and Streptomyces; and ii) determine the role of these proteins in resistance to CAMPs of the human immune system and other antimicrobial agents.

细菌对抗菌剂的耐药性是影响人类健康的最大挑战之一。许多 细菌开发的抗性机制涉及适应导致的细胞壁成分 与抗菌化合物的相互作用降低或渗透性。一种这样的机制使用氨基 由TRNA携带的酸（AA），氨基酰胺磷脂酰甘油（PG），这是该氨基酰基磷脂酰甘油（PG），这是 细菌膜。自从最初发现该途径以来，研究表明脂质氨基酰基化 酶（通常称为氨基酰基磷脂酰甘油合酶； AAPGSS）是令人惊讶的 各种各样的曲目中有几个AA，以改变细菌膜的化学构成。 许多研究表明，PG氨基酰化增强了对抗生素的细菌抗性， 靶向膜（例如阳离子抗菌肽，营地）以及病原体的毒力 来自多个门（即企业和蛋白质细菌）。但是，脂质修饰系统已经 在静脉细菌中很大程度上忽略了，这是一个重要的细菌门，包括主要的病原体 对人类健康的重要性，例如结核病，白喉，诺卡症和 放线菌病。广泛的基因组分析表明，该门中的细菌经常具有多重 （最多六个）AAPGS同源物，表明肌动杆菌的功能多样性很高 脂质修饰系统。我们的初步研究证实了这一假设，导致了几个 在Corynebacteria中的新型脂质修饰系统对于抗菌耐药性很重要和 毒力。静脉细菌中众多其他脂质修饰酶尚待描述，我们 假设其中一些蛋白质也支持新功能。这些研究很重要，因为 AAPGSS代表膜适应的一般因素，并在极端物种中表达 对人类健康的重要性。新型脂质修饰的识别不仅会增加我们的理解 基本的细菌防御机制，但会揭示出抗菌剂发展的新目标 化合物。 我们的长期目标是定义细菌物种脂质修饰的曲目以及 表征它们在细胞生理，抗菌耐药性和发病机理中的作用。这个目的 提案将为以后的研究奠定基础，是i）探索AAPGS同源性的多样性 静脉细菌并表征人类病原体的代表性酶的生化功能 在分枝杆菌，诺卡氏菌，犀牛和链霉菌中； ii）确定这些作用 对人免疫系统和其他抗菌剂的耐药性的蛋白质。

项目成果

The MprF homolog LysX synthesizes lysyl-diacylglycerol contributing to antibiotic resistance and virulence.

• DOI: 10.1128/spectrum.01429-23
• 发表时间: 2023-09-28
• 期刊: MICROBIOLOGY SPECTRUM
• 影响因子: 3.7
• 作者: Gill, Cameron P.;Phan, Christopher;Platt, Vivien;Worrell, Danielle;Andl, Thomas;Roy, Herve
• 通讯作者: Roy, Herve

Synthesis of aminoacylated ergosterols: A new lipid component of fungi

• DOI: 10.1016/j.steroids.2021.108823
• 发表时间: 2021-03
• 期刊: Steroids
• 影响因子: 2.7
• 作者: Daisuke Yokokawa;S. Tatematsu;Ryoka Takagi;Yusuke Saga;H. Roy;Frédéric Fischer;H. Becker;T. Kushiro

RNA-dependent sterol aspartylation in fungi.

真菌中 RNA 依赖性甾醇天冬氨酸化。

• DOI: 10.1073/pnas.2003266117
• 发表时间: 2020
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Yakobov,Nathaniel;Fischer,Frédéric;Mahmoudi,Nassira;Saga,Yusuke;Grube,ChristopherD;Roy,Hervé;Senger,Bruno;Grob,Guillaume;Tatematsu,Shunsuke;Yokokawa,Daisuke;Mouyna,Isabelle;Latgé,Jean-Paul;Nakajima,Harushi;Kushiro,Tetsuo;Becke
• 通讯作者: Becke