Molecular Mechanisms Of Daptomycin Resistance In Enterococci

肠球菌达托霉素耐药的分子机制

• 批准号: 8293053
• 负责人: Cesar Augusto Arias
• 金额: $ 42.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8293053
• 关键词: Adverse effects; Affect; Ampicillin; Antibiotic Resistance; Antibiotics; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Applications Grants; Bacteria; Biological Preservation; Calcium; Cardiolipins; Case Study; Cell Wall; Cell membrane; Charge; Clinical; Combined Modality Therapy; Daptomycin; Data; Development; Dose; Drug resistance; Enterococcus; Enterococcus faecalis; Enzymes; Evaluation; Event; Evolution; FDA approved; Foundations; Future; Gene Components; Genes; Genetic; Genome; Genomics; Genus staphylococcus; Goals; Homeostasis; Homologous Gene; Hospitals; Imagery; Immune system; In Vitro; Infection; Infective endocarditis; Intervention; Investigation; Label; Laboratories; Lead; Linezolid; Mediating; Modeling; Modification; Molecular; Multi-Drug Resistance; Mus; Mutation; Organism; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Phospholipid Metabolism; Phospholipids; Property; Public Health; Pulsed-Field Gel Electrophoresis; Rattus; Regimen; Regulation; Resistance; Resistance development; Resources; Rifampin; Role; Specific qualifier value; System; Testing; Therapeutic; Vancomycin resistant enterococcus; antimicrobial; antimicrobial drug; antimicrobial peptide; bactericide; base; biological adaptation to stress; cardiolipin synthase; cell envelope; comparative; design; improved; in vivo; information gathering; innovation; insight; killings; member; mutant; novel; pathogen; phosphoric diester hydrolase; prevent; quinupristin-dalfopristin; resistance allele; response; tigecycline

DESCRIPTION (provided by applicant): The emergence of antibiotic resistant bacteria is one of the most challenging public health problems affecting humankind in the 21st century. Among these bacteria, vancomycin-resistant enterococci (VRE) are one of the most difficult organisms to treat in hospitals across the US. Only two antimicrobial compounds are currently FDA-approved for the treatment of VRE infections; namely, linezolid and quinupristin-dalfopristin (Q/D). However, the use of these two agents against VRE has been hampered by suboptimal therapeutic outcomes in severe infections, frequent occurrence of side effects and the emergence and widespread dissemination of linezolid- and Q/D-resistant VRE isolates. Daptomycin (DAP) is a lipopeptide antibiotic whose mechanism of killing involves the interaction with the bacterial cell membrane (CM) in a calcium-dependent manner. DAP is the only bactericidal antibiotic currently available with activity against VRE. Although DAP does not have an FDA-approved indication for the treatment of VRE infections, clinicians are often pushed to use DAP due to the lack of better alternatives to treat patients infected with VRE who are often severely ill and with important compromise of the immune system. The off-label use of DAP during VRE therapy has led in several instances to the development of DAP resistance (DAP-R), thus, worsening the clinical scenario even further. Our long- term goal for this grant application is to understand the molecular events that lead to the development of DAP- R during VRE therapy to be able to i) design improved therapeutic strategies to prevent the emergence of DAP-R, and ii) identify new potential targets for antimicrobial development in the future with the aim of protecting the efficacy of DAP against VRE. Based on the information gathered from the comparative whole- genome, CM and cell envelope ultrastructural analysis of VRE clinical strain pairs of DAP-susceptible and DAP-resistant Enterococcus faecalis (VREfs) and E. faecium (VREfm), we have identified two genes that are highly likely to be involved in the development of DAP-R: i) a gene (cls) encoding a cardiolipin synthase enzyme in both VREfs and VREfm, involved in cell membrane homeostasis and ii) a VREfs homolog of the liaF gene, which is part of a three-component gene system involved in the bacterial cell envelope response to antimicrobials and antimicrobial peptides. Thus, we aim to a) investigate the contribution of mutations in the above genes (cls in both VREfs and VREfm and liaF in VREfs) to DAP-resistance, and b) evaluate strategies to optimize the use of DAP for VRE by testing the effect of escalating doses of DAP and combination therapies of DAP with i) ampicillin (for VREfs), and ii) with tigecycline or rifampin (for VREfm), in preventing emergence of DAP-R using a murine model of infective endocarditis. We anticipate that these studies will contribute to a deeper understanding of the role of CM phospholipid homeostasis and cell envelope regulation in the development of antibiotic resistance and antimicrobial peptide action and will certainly facilitate the preservation of DAP as a useful antibiotic to treat VRE infections in the future.

描述（由申请人提供）：抗生素耐药细菌的出现是影响21世纪人类的最具挑战性的公共卫生问题之一。在这些细菌中，抗性霉素肠球菌（VRE）是美国医院中最困难的生物之一。目前，FDA批准了两种抗菌化合物，用于治疗VRE感染。也就是说，lineZolid和quinupristin-dalfopristin（Q/D）。但是，在严重感染，频繁发生副作用以及linezolid-和Q/d抗性VRE分离株中的出现和广泛传播中，对这两种药物对VRE的使用受到了次优的治疗结果的阻碍。 Daptomycin（DAP）是一种脂蛋白抗生素，其杀死的机制涉及以钙依赖性方式与细菌细胞膜（CM）的相互作用。 DAP是目前与VRE活性相关的唯一杀菌抗生素。尽管DAP没有通过FDA批准的指征来治疗VRE感染，但由于缺乏治疗患者感染的VRE的更好替代品，通常会严重疾病，并且受到重要的损害，临床医生通常会使用DAP使用DAP。 。在VRE治疗期间，DAP的标签不使用已导致DAP耐药性（DAP-R）的发展，从而使临床情况更加恶化。我们对该赠款应用的长期目标是了解导致VRE治疗期间DAPR发展的分子事件，以便i）设计改进的治疗策略以防止DAP-R的出现，ii）确定未来抗菌发育的新潜在靶标，目的是保护DAP对VRE的功效。基于从比较全基因组中收集的信息，CM和细胞包膜超结构分析的VRE临床应变对的DAP敏感和抗DAP耐药的肠球菌（VREFS）（VREFS）和E.粪便（VREFM），我们已经鉴定了两个基因很可能参与DAP-R的开发：i）在VREF和VREFM中编码心磷脂合酶的基因（Cls），参与细胞膜稳态和II），vrefs的LIAF基因同源物，这是参与细菌细胞包膜响应抗菌和抗菌肽的三成分基因系统的一部分。因此，我们的目的是a）研究上述基因中突变的贡献（VREFS和VREFM和LIAF中的CL）对DAP耐药性的贡献，b）评估策略，通过测试效果来优化DAP的使用，以优化DAP的使用，以实现效果。 DAP与i）氨苄青霉素（用于VREFS）的DAP剂量和组合疗法的升级剂量，以及II）使用Tigecycline或Rifampin（对于VREFM）（用于VREFM），以防止使用感染性心内心动炎的鼠模型出现DAP-R。我们预计，这些研究将有助于更深入地了解CM磷脂稳态和细胞包膜调节在抗生素耐药性发展和抗菌肽作用中的作用未来。