Does ampicillin resistance or clade type determine GI colonization by E. faecium?

氨苄西林耐药性或进化枝类型是否决定了屎肠球菌在胃肠道的定植？

• 批准号: 8427005
• 负责人: BARBARA E MURRAY
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427005
• 关键词: Accounting; Acinetobacter; Alleles; Ampicillin; Ampicillin Resistance; Antibiotic Resistance; Antibiotics; Bile fluid; Biological; Cephalosporin Resistance; Clinical; Communities; Complex; Critical Illness; DNA Sequencing Facility; Development; Disease Outbreaks; Distant; Ecological Change; Elements; Endocarditis; Enterobacter; Enterococcus faecalis; Enterococcus faecium; Evolution; Feces; Frequencies; Future; Gastrointestinal tract structure; Genes; Genome; Genomics; Genus staphylococcus; Goals; Healthcare; Hospitals; Immunocompromised Host; Individual; Infection; Infection prevention; Intestines; Klebsiella; Lactams; Lead; Link; Methodology; Mobile Genetic Elements; Modeling; Molecular; Mono-S; Monobactams; Mucositis; Multi-Drug Resistance; Mus; Nature; Organism; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Play; Prevention strategy; Pseudomonas; Public Health; Publications; Resistance; Role; Sorting - Cell Movement; Time; Translating; Vancomycin Resistance; Vancomycin resistant enterococcus; Virulence Factors; Virulent; Volunteer Group; acronyms; base; chemotherapy; density; drug resistant bacteria; experience; fitness; healthy volunteer; insight; prevent; public health relevance; research study; resistant strain

DESCRIPTION (provided by applicant): Enterococcus faecium (Efm) caused very few infections in the past but these have increased markedly in recent years, including endocarditis and other serious infections, some of which are medically untreatable (e.g., >80% of nosocomial Efm are vancomycin resistant (VRE), almost all of which are ampicillin resistant, the traditional drugs of choice). This led to Efm's inclusion in the group of "bad bugs" from which we seem to have "no ESKAPE". The factors behind the shift of Efm from "commensal" to "pathogenic" are not well understood but antibiotic resistance, mobile genetic elements and/or genes conferring increased pathogenicity or fitness have been blamed, since such genes are more commonly found in the Efm clonal complexes that account for almost all outbreak/nosocomial (hospital-associated (HA)) isolates. Our recent genomic comparisons showed that the species Efm consists of 2 distinct clades whose core gene sequences differ by >4%. Almost all HA Efm belong to one (HA) clade whereas almost all community-associated (CA) isolates from healthy volunteers group in the other (CA) clade; such core gene differences are not observed in E. faecalis although it too has HA clonal complexes. We also found that pbp5 is a core gene that encodes, in HA-clade strains, PBP5-R (ampicillin resistance) and varies from PBP5-S (ampicillin MICs <4) of CA-clade isolates by ~5%. Our molecular clock estimates indicate that the 2 clades diverged long before (300,000 ~ e1 million years) the modern antibiotic era. Thus, the recent increase of nosocomial Efm is due to replacement of CA by HA strains, rather than, as had been suggested, recent evolution within community-predominant (CA) strains. However, it is not clear what explains this replacement, why HA strains are seldom seen in healthy volunteers nor if HA isolates are more pathogenic. Perhaps CA strains actually colonize better, explaining their vast predominance in community feces, and perhaps it is simply the antibiotic resistance of the HA clade that allows its isolates to overcome CA isolates, grow to high density and then cause infections in the healthcare setting. An inherent difference between these 2 clades is resistance to ampicillin; of note, HA-clade ampicillin-resistant strains (which are also highly cephalosporin resistant) preceded nosocomial VRE emergence worldwide. The hypothesis of this proposal is that the core genome, and perhaps entirely pbp5-R of the HA clade, has allowed this clade to replace CA strains in patients receiving ?-lactams. In Aim 1, we will investigate which colonize better: HA-clade Efm strains or CA-clade Efm strains, and then determine the impact of ?-lactam use on promoting colonization by HA-clade isolates (PBP5-R) over CA isolates (PBP5-S) in the mouse GI colonization model. In Aim 2, we will examine the specific role of pbp5 alleles in Efm colonization during ?-lactam use by swapping pbp5-S and -R between CA and HA strains. The results could open new avenues for preventing infection or, if HA strains colonize better than CA ones even without ?-lactam antibiotics, new avenues to pursue in the future to unravel the contributions of other core and/or acquired genes.

描述（由申请人提供）：肠球菌（Enterococcus faecium, Efm）在过去很少引起感染，但近年来这些感染明显增加，包括心内膜炎和其他严重感染，其中一些是医学上无法治疗的（例如，bbb80 %的院内Efm是万古霉素耐药（VRE），几乎所有的都是氨苄西林耐药，传统药物的选择）。这导致Efm被列入“坏bug”的群体中，我们似乎没有ESKAPE。Efm从“共生”向“致病”转变背后的因素尚不清楚，但人们指责抗生素耐药性、可移动的遗传因素和/或赋予更高致病性或适应性的基因，因为这些基因更常见于几乎所有爆发/医院（医院相关（HA））分离株的Efm克隆复合物中。我们最近的基因组比较表明，Efm物种由2个不同的分支组成，其核心基因序列相差b> %。几乎所有HA Efm都属于一个（HA）分支，而几乎所有来自健康志愿者组的社区相关（CA）分离株都属于另一个（CA）分支；这种核心基因差异在粪肠杆菌中没有观察到，尽管它也有HA克隆复合物。我们还发现，pbp5是ha分支菌株中编码pbp5 - r（氨苄西林耐药）的核心基因，与ca分支分离株的pbp5 - s（氨苄西林mic <4）差异约5%。我们的分子钟估计表明，这两个进化支早在现代抗生素时代（30万~ 100万年前）就分化了。因此，最近医院Efm的增加是由于HA菌株取代了CA，而不是像之前所认为的那样，是社区优势（CA）菌株最近的进化。然而，目前尚不清楚是什么解释了这种替代，为什么在健康志愿者中很少见到血凝素菌株，以及血凝素菌株是否更具致病性。也许CA菌株实际上更好地定植，解释了它们在社区粪便中的巨大优势，也许仅仅是HA分支的抗生素耐药性使得其分离株能够克服CA分离株，生长到高密度，然后在医疗保健环境中引起感染。这两个支系之间的内在差异是对氨苄西林的耐药性；值得注意的是，ha分支的氨苄西林耐药菌株（也对头孢菌素高度耐药）在全世界院内VRE出现之前就出现了。该提议的假设是，核心基因组，可能是HA分支的全部pbp5-R，允许该分支在接受-内酰胺的患者中取代CA菌株。在Aim 1中，我们将研究ha -枝Efm菌株和ca -枝Efm菌株哪个定殖更好，然后确定？在小鼠胃肠道定植模型中，-内酰胺对ha分支分离株（PBP5-R）比CA分离株（PBP5-S）促进定植的作用。在目标2中，我们将研究pbp5等位基因在Efm定殖过程中的具体作用。通过在CA和HA菌株之间交换pbp5-S和-R来使用-内酰胺。结果可能为预防感染开辟新的途径，或者，如果HA菌株比CA菌株更好地定植，即使没有？-内酰胺类抗生素是未来探索其他核心和/或获得性基因贡献的新途径。