Mechanisms and Circumvention of Daptomycin Resistance in Streptococcus mitis

轻链球菌达托霉素耐药机制及规避

• 批准号: 10064598
• 负责人: ARNOLD S BAYER
• 金额: $ 45.66万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-15 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064598
• 关键词: Address; Altruism; Animals; Antibiotic Resistance; Antibiotics; Bacteremia; Blood Circulation; Cancer Patient; Cardiolipins; Cell Death; Cell Separation; Cells; Cephalosporins; Clinical; Collection; Combined Antibiotics; Communicable Diseases; Community Hospitals; Complement; Daptomycin; Data; Development; Enterococcus; Event; Evolution; Failure; Flow Cytometry; Fluorescence Microscopy; Frequencies; Gene Expression Profiling; Genes; Genetic; Genotype; Glycopeptides; Goals; Grant; Heart Valves; High Prevalence; In Vitro; Individual; Infection; Infective endocarditis; Investigation; Mediating; Medical center; Microscopy; Modeling; Mutation; Nosocomial Infections; Organism; Oryctolagus cuniculus; Outcome; Pathogenesis; Penicillin Resistance; Penicillins; Pharmacology; Phenotype; Physiological; Population; Prevention strategy; Regimen; Reporting; Research; Research Personnel; Resistance; Resort; Sepsis; Sepsis Syndrome; Shock; Specialist; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus Viridans Group; Streptococcus mitis; Subgroup; Suicide; Syndrome; System; Therapeutic; Toxic Shock Syndrome; United States National Institutes of Health; Vancomycin; Work; antimicrobial; bactericide; beta-Lactam Resistance; beta-Lactams; clinically significant; conventional therapy; design; emerging pathogen; genomic locus; human pathogen; in vivo; knockout gene; pathogen; prevent; prototype; resistant strain; suicidal; therapy outcome; treatment strategy; trend; uptake; virtual; whole genome

ABSTRACT Viridans group streptococci (VGS), especially Streptococcus mitis, are pivotal pathogens in a variety of invasive endovascular infections,including: i) “breakthrough bacteremias” and “toxic shock” in neutropenic cancer patients; and ii) infective endocarditis (IE). Given world-wide trends in penicillin-resistance and other β-lactam MIC “creeps” amongst S. mitis strains, the proportion of serious infections caused by relatively or fully β-lactam-resistant-(R) strains is disturbing. Moreover, clinical outcomes in such cases utilizing alternate regimens (e.g., vancomycin) have been disappointing, presumably related to the high prevalence of vancomycin “tolerance” in such strains. This has prompted use of newer bactericidal agents, like daptomycin (DAP) for severe S. mitis syndromes in strains with β-lactam-resistance. Alarmingly, recent recognition of rapid, durable and high-level DAP-R induced by DAP therapy has significantly reduced enthusiasm for such approaches. In addition, DAP MICs in the S. mitis group are 2-10-fold higher than all other VGS groups. The number of reported clinical cases of invasive S. mitis infections in which DAP-R has emerged is limited, due to the relatively infrequent use of DAP in such infections to-date. However, progressive rise in S. mitis β-lactam-R plus the inconsistent outcomes of VANC therapy in such syndromes virtually assures increased DAP use, leading to DAP-R S. mitis infections. Moreover, medical centers with high DAP usage have recently confirmed substantial MIC “creeps” amongst enterococci. Understanding mechanism(s) of emergence of DAP-R in S. mitis, plus strategies to circumvent its evolution are, thus, of great clinical significance. Our Preliminary Data showed that DAP-R outcomes in S. mitis are likely to be multifactorial on both phenotypic and genotypic levels. Most interestingly, we have now shown compelling evidence of two forms of “DAP hyperaccumulation” in which individual cells in a given streptococcal chain can hyper-capture DAP and either die (“altruistic suicide”) or resist DAP killing, in order to protect the remainder of the cell population from DAP exposures and lethality. This is an apparently unique mechanism of DAP-R amongst gram-positive pathogens. In this proposal, we will use strategic fluorescence microscopy, flow cytometry with multidimensional physiologic interrogations, and single cell sorting plus genotyping to divulge mechanisms by which DAP-R S. mitis can resist DAP exposures. Finally, we will use two well-characterized models of endovascular infections, ex vivo (chamber model) and in vivo (experimental rabbit IE), to define DAP regimens to both circumvent emergence of DAP-R and enhance clearance of S. mitis. In summary, these studies will divulge clinical strategies to forestall emergence of DAP-R in S. mitis and perhaps other Gram-positive pathogens.

抽象的 Viridans组链球菌（VGS），尤其是Mitis链球菌，是各种关键的病原体 浸润性血管内感染，包括：i）中立的“突破性细菌”和“有毒冲击” 癌症患者； ii）感染性心内膜炎（IE）。鉴于全球耐药性和其他趋势 链球菌菌株中的β-内酰胺MIC“蠕变”，相对或完全完全感染的严重感染比例 β-内酰胺抗性 - （R）菌株令人不安。此外，在这种情况下，临床结果利用替代方案 方案（例如万古霉素）令人失望，大概与高患病率有关 万古霉素在这种菌株中的“耐受性”。这促使使用了较新的杆菌剂，例如daptomycin （DAP）患有β-内酰胺耐药性菌株中严重的甲状腺炎综合征。令人震惊的是，最近对 DAP疗法引起的快速，耐用和高级DAP-R可显着降低对此类的热情 方法。此外，链球菌组中的DAP MIC比所有其他VGS组高2-10倍。这 报告的DAP-R出现的侵袭性链球菌感染的临床病例的数量受到限制 迄今为止，在此类感染中，DAP的相对不经常使用。然而，Mitisβ-LACTAM-R的逐步上升 再加上这种综合症中万物疗法的不一致的结果，实际上假设DAP的使用增加， 导致DAP-R S. Mitis感染。此外，最近使用高点心的医疗中心已确认 肠球菌中大量的麦克风“蠕变”。了解DAP-R在中的出现机制 S. Mitis，以及规避其演变的策略具有极大的临床意义。 我们的初步数据表明，链球菌中的DAP-R结果可能是多因素的 表型和基因型水平。最有趣的是，我们现在显示了两种形式的令人信服的证据 “ DAP高蓄能”，其中给定链球菌链中的单个细胞可以超捕获DAP，并且 为了保护其余的细胞种群，死亡（“无私自杀”）或抵抗DAP杀害 DAP暴露和致死性。这是革兰氏阳性中DAP-R的明显独特机制 病原体。 在此提案中，我们将使用具有多维的战略荧光显微镜，流式细胞仪 生理询问和单细胞分类以及DAP-R的剥离机制的基因分型 S. mitis可以抵抗DAP暴露。最后，我们将使用两种良好的内血管内模型 感染，离体模型（室模型）和体内（实验兔IE），以将DAP方案定义为两者 规避DAP-R的出现并增强了Mitis的清除率。总而言之，这些研究将泄露 临床策略，以阻止Mitis和其他革兰氏阳性病原体中DAP-R出现。