Mechanisms of Staphylococcal Co-Resistance to Daptomycin and Host Defense Peptide

葡萄球菌对达托霉素和宿主防御肽的共耐药机制

• 批准号: 8843328
• 负责人: ARNOLD S BAYER
• 金额: $ 35.4万
• 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: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843328
• 关键词: Address; Antibiotics; Antimicrobial Cationic Peptides; Antisense RNA; Applications Grants; Binding; Biochemical; Blood Platelets; Calcium; Cell membrane; Charge; Clinical; Consensus; Daptomycin; Development; Event; Evolution; Exhibits; Exposure to; Frequencies; Future; Gene Expression; Gene Mutation; Genes; Genetic Polymorphism; Host Defense; Hydrophobicity; In Vitro; Individual; Infection; Infective endocarditis; Light; Mediating; Methicillin Resistance; Modeling; Molecular; Molecular Profiling; Multi-Drug Resistance; Mutation; Pathogenesis; Peptides; Phenotype; Phospholipids; Plasmids; Proteins; R peptide; Relative (related person); Reporting; Resistance; Role; Schedule; Seminal; Serial Passage; Site; Staphylococcus aureus; Structure; Surface; Syndrome; System; Time; Tissues; Treatment Protocols; Treatment outcome; Virulence; antimicrobial; attributable mortality; design; gene function; in vivo; methicillin resistant Staphylococcus aureus; novel; resistance factors; resistant strain; response

DESCRIPTION (provided by applicant): S. aureus (SA) causes a wide spectrum of clinical syndromes, and is the leading cause of endovascular infections world-wide. SA has a particular propensity to develop multi-drug resistance, and serious infections with such strains result in enhanced attributable mortalities. Since FDA approval in 2003, daptomycin (DAP) has been utilized in many clinical settings, especially for recalcitrant methicillin-resistant SA (MRSA) infections. There have been numerous recent reports of clinical SA strains that have evolved in vitro DAP-resistance in the context of failing DAP treatment regimens, especially in endovascular infections. One consistent feature of DAP-R strains is the acquisition of one or more "gain-in-function" mutations in a relatively restricted cadre of genes, especially mprF (multiple peptide resistance factor gene). This gene is responsible for the synthesis and translocation ("flipping") of the SA-unique, positively-charged phospholipid (PL), lysyl-phosphotidylglycerol (L-PG) within its cell membrane (CM). Thus, mprF contributes substantially to the relative positive surface charge of SA. Moreover, in light of the absolute requirement for calcium association for DAP's bacterial lethality, genes such as mprF that impact surface charge are highly likely to be important in DAP-R, potentially via charge repulsion. A seminal feature of both clinical and in vitro-derived DAP-R SA strains is the frequent cross-resistance between DAP and cationic host defense peptides (HDPs) (13,15,17-19). Thus, our central hypothesis is that the development of DAP- R in MRSA is frequently associated with the co-evolution of HDP resistance, and this event impacts endovascular pathogenesis and treatment outcomes in vivo. We will address a number of important questions: i) how often do mprF gain-in-function mutations accompany DAP-HDP cross-resistance phenotypes?; ii) are such mprF mutations biased towards the synthase or flippase domains of this gene, and are they causal in cross-resistance?; iii) are there HDP- specific structural features that are shared amongst those peptides which exhibit the DAP-HDP cross-resistance phenotype?; iv) does the temporal exposure "schedule" of S. aureus strains to DAP and/or HDPs influence the development of cross-resistance?; and vi) what are the in vivo consequences of mprF mutations and DAP-HDP cross resistances upon innate virulence and responses to DAP therapy? We anticipate that these studies will contribute to a deeper understanding of the interactive role of our innate host defense system with exogenously administered antimicrobials in stimulating the adaptive survival response in SA. This should enable 'smart design' of future novel anti-SA agents that circumvent this adaptive response.

描述（由申请人提供）：金黄色葡萄球菌（SA）引起广泛的临床综合征，是世界范围内血管内感染的主要原因。SA特别倾向于产生多药耐药，这种菌株的严重感染导致可归因死亡率增加。自2003年FDA批准以来，达托霉素（DAP）已用于许多临床环境，特别是难治性耐甲氧西林SA （MRSA）感染。最近有许多关于临床SA菌株在DAP治疗方案失败的情况下进化出体外DAP耐药性的报道，特别是在血管内感染中。DAP-R菌株的一个一致特征是在相对有限的基因主干中获得一个或多个“功能获得”突变，特别是mprF（多肽耐药因子基因）。该基因负责sa独特的、带正电的磷脂（PL）、赖基磷脂酰甘油（L-PG）在细胞膜（CM）内的合成和易位（“翻转”）。因此，mprF对SA的相对正表面电荷有很大贡献。此外，鉴于DAP的细菌致死率绝对需要钙结合，影响表面电荷的基因如mprF很可能在DAP- r中很重要，可能通过电荷排斥作用。临床和体外衍生的DAP- r SA菌株的一个重要特征是DAP与阳离子宿主防御肽（hdp）之间频繁的交叉耐药（13,15,17-19）。因此，我们的中心假设是MRSA中DAP- R的发展经常与HDP耐药的共同进化相关，并且这一事件影响血管内发病机制和体内治疗结果。我们将解决一些重要的问题：i) mprF功能增益突变伴随DAP-HDP交叉抗性表型的频率是多少？ii)这些mprF突变是否偏向于该基因的合成酶或翻转酶结构域，它们是否导致交叉抗性？iii)在表现出DAP-HDP交叉抗性表型的肽中是否存在HDP特异性结构特征？iv)金黄色葡萄球菌菌株对DAP和/或HDPs的时间暴露“时间表”是否影响交叉耐药性的发展？以及vi) mprF突变和DAP- hdp交叉耐药对先天毒力和对DAP治疗反应的体内影响是什么？我们预计这些研究将有助于更深入地了解我们的先天宿主防御系统与外源性给药抗菌剂在刺激SA适应性生存反应中的相互作用。这将使未来新型抗sa药物的“智能设计”成为可能，以规避这种适应性反应。