Abdelhady Wessam, Chen Liang, Bayer Arnold S, Seidl Kati, Yeaman Michael R, Kreiswirth Barry N, Xiong Yan Q
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
Public Health Research Institute, NJMS-Rutgers University, Newark, NJ, USA.
J Antimicrob Chemother. 2015 May;70(5):1443-52. doi: 10.1093/jac/dku547. Epub 2015 Jan 5.
Persistent MRSA infections are especially relevant to endovascular infections and correlate with suboptimal outcomes. However, the virulence signatures of Staphylococcus aureus that drive such persistence outcomes are not well defined. In the current study, we investigated correlations between accessory gene regulator (agr) activation and the outcome of vancomycin treatment in an experimental model of infective endocarditis (IE) due to MRSA strains with different agr and clonal complex (CC) types.
Twelve isolates with the four most common MRSA CC and agr types (CC5-agr II, CC8-agr I, CC30-agr III and CC45-agr I) were evaluated for heterogeneous vancomycin-intermediate S. aureus (hVISA), agr function, agrA and RNAIII transcription, agr locus sequences, virulence and response to vancomycin in the IE model.
Early agr RNAIII activation (beginning at 2 h of growth) in parallel with strong δ-haemolysin production correlated with persistent outcomes in the IE model following vancomycin therapy. Importantly, such treatment failures occurred across the range of CC/agr types studied. In addition, these MRSA strains: (i) were vancomycin susceptible in vitro; (ii) were not hVISA or vancomycin tolerant; and (iii) did not evolve hVISA phenotypes or perturbed δ-haemolysin activity in vivo following vancomycin therapy. Moreover, agr locus sequence analyses revealed no common point mutations that correlated with either temporal RNAIII transcription or vancomycin treatment outcomes, encompassing different CC and agr types.
These data suggest that temporal agr RNAIII activation and agr functional profiles may be useful biomarkers to predict the in vivo persistence of endovascular MRSA infections despite vancomycin therapy.
持续性耐甲氧西林金黄色葡萄球菌（MRSA）感染与血管内感染尤其相关，且与欠佳的治疗结果相关。然而，导致此类持续性结果的金黄色葡萄球菌的毒力特征尚未明确界定。在本研究中，我们在一个感染性心内膜炎（IE）实验模型中，研究了辅助基因调节子（agr）激活与万古霉素治疗结果之间的相关性，该模型使用了具有不同agr和克隆复合体（CC）类型的MRSA菌株。
评估了12株具有四种最常见的MRSA CC和agr类型（CC5-agr II、CC8-agr I、CC30-agr III和CC45-agr I）的菌株，检测其异质性万古霉素中介金黄色葡萄球菌（hVISA）、agr功能、agrA和RNAIII转录、agr基因座序列、毒力以及在IE模型中对万古霉素的反应。
在万古霉素治疗后的IE模型中，早期agr RNAIII激活（在生长2小时时开始）并伴有强烈的δ-溶血素产生与持续性结果相关。重要的是，在所研究的CC/agr类型范围内均出现了此类治疗失败情况。此外，这些MRSA菌株：（i）在体外对万古霉素敏感；（ii）不是hVISA或耐万古霉素菌株；（iii）在万古霉素治疗后体内未出现hVISA表型或δ-溶血素活性改变。而且，agr基因座序列分析未发现与RNAIII转录时间或万古霉素治疗结果相关的常见点突变，涵盖了不同的CC和agr类型。
这些数据表明，尽管进行了万古霉素治疗，但agr RNAIII的激活时间和agr功能谱可能是预测血管内MRSA感染体内持续性的有用生物标志物。
