Molecular Mechanisms Of Daptomycin Resistance In Enterococci

肠球菌达托霉素耐药的分子机制

• 批准号: 8874852
• 负责人: Cesar Augusto Arias
• 金额: $ 28.67万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874852
• 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; Genomic approach; 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; genetic approach; improved; in vivo; information gathering; innovation; insight; killings; member; multi-drug resistant pathogen; 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21世纪影响人类的最具挑战性的公共卫生问题之一。在这些细菌中，耐万古霉素肠球菌 (VRE) 是美国医院中最难治疗的微生物之一。目前只有两种抗菌化合物获得 FDA 批准用于治疗 VRE 感染；即利奈唑胺和奎奴普汀-达福普汀（Q/D）。然而，这两种药物对抗 VRE 的使用受到了严重感染时治疗效果欠佳、副作用频繁发生以及利奈唑胺和 Q/D 耐药 VRE 菌株的出现和广泛传播的阻碍。达托霉素 (DAP) 是一种脂肽抗生素，其杀伤机制涉及以钙依赖性方式与细菌细胞膜 (CM) 相互作用。 DAP 是目前唯一具有对抗 VRE 活性的杀菌抗生素。尽管 DAP 没有 FDA 批准的用于治疗 VRE 感染的适应症，但由于缺乏更好的替代方案来治疗 VRE 感染患者，而这些患者通常病情严重且免疫系统严重受损，因此临床医生经常被迫使用 DAP。 VRE 治疗期间超说明书使用 DAP 已多次导致 DAP 耐药性 (DAP-R) 的发展，从而进一步恶化临床情况。我们本次拨款申请的长期目标是了解在 VRE 治疗期间导致 DAP-R 发展的分子事件，以便能够 i) 设计改进的治疗策略以防止 DAP-R 的出现，以及 ii) 确定未来抗菌药物开发的新潜在目标，以保护 DAP 对抗 VRE 的功效。基于对 DAP 敏感和 DAP 抗性粪肠球菌 (VREfs) 和屎肠球菌 (VREfm) VRE 临床菌株对的比较全基因组、CM 和细胞包膜超微结构分析收集的信息，我们鉴定了两个极有可能参与 DAP-R 发育的基因： i) 编码心磷脂的基因 (cls) VREfs 和 VREfm 中的合酶，参与细胞膜稳态；ii) liaF 基因的 VREfs 同源物，该基因是三组分基因系统的一部分，参与细菌细胞包膜对抗菌剂和抗菌肽的反应。因此，我们的目标是 a) 研究上述基因突变（VREfs 和 VREfm 中的 cls 以及 VREfs 中的 liaF）对 DAP 耐药性的贡献，b) 通过测试 DAP 剂量递增以及 DAP 与 i) 氨苄西林（针对 VREfs）和 ii) 替加环素联合治疗的效果，评估优化 DAP 用于 VRE 的策略 或利福平（用于 VREfm），使用感染性心内膜炎小鼠模型预防 DAP-R 的出现。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发展中的作用，并且必将有助于保留 DAP 作为未来治疗 VRE 感染的有用抗生素。

项目成果

A new antibiotic and the evolution of resistance.

• DOI: 10.1056/nejmcibr1500292
• 发表时间: 2015-03-19
• 期刊: The New England journal of medicine
• 作者: Arias CA;Murray BE
• 通讯作者: Murray BE

Cefazolin high-inoculum effect in methicillin-susceptible Staphylococcus aureus from South American hospitals.

头孢唑林对南美医院甲氧西林敏感金黄色葡萄球菌的高接种效果。

• DOI: 10.1093/jac/dkt254
• 发表时间: 2013
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Rincón,Sandra;Reyes,Jinnethe;Carvajal,LinaPaola;Rojas,Natalia;Cortés,Fabián;Panesso,Diana;Guzmán,Manuel;Zurita,Jeannete;Adachi,JavierA;Murray,BarbaraE;Nannini,EstebanC;Arias,CesarA
• 通讯作者: Arias,CesarA

[Resistance to "last resort" antibiotics in Gram-positive cocci: The post-vancomycin era].

• DOI: 10.1590/s0120-41572014000500022
• 发表时间: 2014-04
• 期刊: Biomedica : revista del Instituto Nacional de Salud
• 作者: Rincón S;Panesso D;Díaz L;Carvajal LP;Reyes J;Munita JM;Arias CA
• 通讯作者: Arias CA

Treatment of extended-spectrum Beta-lactamase enterobacteriaceae with cefepime: the dose matters, too.

用头孢吡肟治疗超广谱 β-内酰胺酶肠杆菌：剂量也很重要。

• DOI: 10.1093/cid/cit383
• 发表时间: 2013
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Altshuler,Jerry;Aitken,SamuelL;Guervil,David;Esaian,Diana;Papadopoulos,John;Arias,CesarA
• 通讯作者: Arias,CesarA

Enterococcal endocarditis: can we win the war?

• DOI: 10.1007/s11908-012-0270-8
• 发表时间: 2012-08
• 期刊: CURRENT INFECTIOUS DISEASE REPORTS
• 影响因子: 3.1
• 作者: Munita, Jose M.;Arias, Cesar A.;Murray, Barbara E.
• 通讯作者: Murray, Barbara E.