Novel antibiotic resistance mechanisms in S. aureus

描述(申请者提供)：金黄色葡萄球菌引起错位 美国的死亡率和经济损失。我们描述了一种水杨酸盐诱导的多药 金黄色葡萄球菌的耐药机制。水杨酸盐诱导的多药耐药表达 表型，并涉及减少药物积累。以前金黄色葡萄球菌的内在多药耐药性被归因于多药外排泵NorA。我们提供的证据表明，水杨酸盐诱导的多药耐药机制是非依赖的。我们还将描述一种金黄色葡萄球菌的多药耐药机制，这是对抗微生物萜类混合物Pinesol进行抗性选择的结果。这一机制也增加了对细胞壁活性的抗葡萄球菌抗生素万古霉素的耐药性。我们打算确定可能的金黄色葡萄球菌多药外排泵AcrB和/或替代转录因子sigma B是否在我们实验室正在研究的金黄色葡萄球菌多药耐药机制中发挥作用。我们还计划证明松醇选择的多药耐药突变体和水杨酸处理的细胞表达改变的细胞壁生理。与松醇选择和水杨酸诱导的金黄色葡萄球菌多药耐药机制相关的基因将通过两个程序进行鉴定：双向凝胶电泳法和DNA亚阵列，其中包括与金黄色葡萄球菌多药耐药相关的基因。我们推测金黄色葡萄球菌的多药耐药表达将涉及大量的基因和基因产物。我们还假设金黄色葡萄球菌可能的多药外排泵AcrB和替代转录因子sigma B将在金黄色葡萄球菌的多药耐药性表达中发挥作用。2.正常金黄色葡萄球菌细胞；松树选育的金黄色葡萄球菌突变体；水杨酸诱导的金黄色葡萄球菌细胞。与金黄色葡萄球菌内在多药耐药机制相关的新成分可能被用作开发抗微生物药物的靶点，用于预防耐药金黄色葡萄球菌的产生或阻止与活动性疾病有关的金黄色葡萄球菌的生长。这项研究还将有助于不断增长的关于革兰氏阳性球菌细胞与杀菌剂和抗生素相互作用的知识。

DESCRIPTION (provided by applicant): Staphylococcus aureus is responsible for staggering mortality and financial loss in the U.S. We have characterized a salicylate-inducible multidrug resistance mechanism in S. aureus. Salicylate-induced multidrug resistance is expressed phenotypically and involves reduced drug accumulation. Previously intrinsic multidrug resistance in S. aureus was attributed to the multidrug efflux pump NorA. We provide evidence that demonstrates that the salicylate-induced multidrug resistance mechanism is NorA-independent. We will also characterize a genotypic S. aureus multidrug resistant mechanism that results as a consequence of selection for resistance to the antimicrobial terpene mixture pinesol. This mechanism also increases resistance to the cell wall active antistaphylococcal antibiotic vancomycin. We intend to determine if the putative S. aureus multidrug efflux pump AcrB and/or the alternative transcription factor sigma B play roles in the multidrug resistance mechanisms of S. aureus being studied in our laboratories. We also plan to demonstrate that pinesol-selected multidrug resistant mutants and salicylate treated cells express altered cell wall physiology. Genes involved with pinesol-selected and salicylate-inducible multidrug resistance mechanisms of S. aureus will be identified using two procedures: Two-dimensional gel electrophoresis and a DNA subarray constructed with genes suspected to be associated with multidrug resistance in S. aureus. We hypothesize that multidrug resistance expression by S. aureus will involve a large collection of genes and gene products. We also hypothesize that the putative multidrug efflux pump AcrB and alternative transcription factor sigma B of S. aureus will play a role in the multidrug resistance expression of: i.) normal S. aureus cells; ii.) pinesol-selected mutants of S. aureus; and iii.) salicylate-induced S. aureus cells. Novel components associated with intrinsic multidrug resistance mechanisms in S. aureus might be used as targets in the development of antimicrobials used to either prevent antibiotic resistant S. aureus from arising or to halt the growth of S. aureus involved with active disease. This research will also contribute to the growing body of knowledge on the interaction of the Gram-positive coccal cells with biocides and antibiotics.