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患者的替代方案缺乏更好的替代品，这些临床医生通常会使用DAP，这些患者经常严重患病并且对免疫系统的重要损害。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治疗过程中DAP-R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目标，以保护DAP的效率。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对DAP敏感和抗DAP抗DAP的肠球菌（VREFS）（VREFS）（VREFS）和E.粪肠球菌（VREFM）的临床应变对（VREFM），我们已经确定了两种基因，这些基因很可能与DAP-RENS coldin cod of Dap-R相关。 VREF和VREFM中的合酶，涉及细胞膜稳态和II）LIAF基因的VREFS同源物，该基因是与细菌细胞包膜响应抗微生物和抗菌肽的三组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VREF中的VREF和LIAF中的Cls）对DAP耐药性的贡献，以及b）评估策略，通过测试dap and dap and ii dap and ampicillis（ii）ampicillin（I）ampicillin（i）的效果，以优化DAP对VRE的使用来优化DAP，以实现VRE的效果，以实现II）（i）ampicillin（i）ampicillin（I）ampicillin（i）。或利福平（对于VREFM），在使用感染性心内膜炎的鼠模型中防止DAP-R出现。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和抗菌肽作用中的发育中的作用，并且肯定会在将来将DAP作为一种有用的DAP保存，以将其作为一种有用的抗生素来处理VRE的未来感染。