Molecular genetics and evolution of antibiotic resistant staphylococci

由金黄色葡萄球菌（俗称金葡萄球菌）引起的潜在威胁生命的感染，经常在医院内的患者中出现并发症。这些感染损害了患者的健康，并危及他们从最初入院时的病情中恢复过来，这大大增加了医疗保健费用。金黄色葡萄球菌是澳大利亚和全球医院获得性感染的主要原因。这一问题主要是由于医院中存在对大多数临床有用的抗生素具有耐药性的菌株，因此很难根除；最近分离出的对最后一种抗葡萄球菌抗生素万古霉素高度耐药的菌株尤其令人担忧。这些多重耐药菌株的出现主要是由于细胞间基因转移获得了预先存在的耐药决定因素，在这一过程中，质粒，染色体外DNA元件，起着突出的作用。葡萄球菌多重耐药质粒携带的基因可使其对多达20种抗菌素产生耐药性，并且本身能够在细菌细胞之间转移。在这个项目中，我们将定义葡萄球菌多重耐药质粒在宿主细胞中有效复制并在不断增长的细菌群体中或在转移后被新宿主获得时稳定维持的分子机制；这种机制很可能提供新的药物靶点。该结果还将导致改进临床菌株特征和抗生素耐药性监测方法的发展，并且将与细菌病原体的抗菌素耐药性问题具有广泛的相关性。最重要的是，将这些研究产生的知识应用于合理抗生素使用政策的设计和实施，有可能扩大现有和未来抗葡萄球菌治疗的疗效。

Potentially life-threatening infections caused by Staphylococcus aureus bacteria, commonly known as Golden Staph, often arise as complications in patients within hospitals. These infections compromise the health of the patient and jeopardise their recovery from the condition for which they were initially admitted, which significantly increases healthcare costs. Golden Staph is a major cause of hospital-acquired infections in Australia and globally. The problem is largely due to the presence in hospitals of strains that are resistant to most clinically-useful antibiotics and are therefore very difficult to eradicate; the recent isolation of strains highly-resistant to one of the last resort anti-staphylococcal antibiotics, vancomycin, is particularly worrying. The emergence of these multiresistant strains is primarily attributable to the acquisition of pre-existing resistance determinants by cell-to-cell gene transfer, a process in which plasmids, extra-chromosomal DNA elements, play a prominent role. Staphylococcal multiresistance plasmids carry genes that can confer resistance to up to 20 antimicrobial agents and are themselves capable of transfer between bacterial cells. In this project, we will define the molecular mechanisms by which staphylococcal multiresistance plasmids efficiently replicate in the host cell and are stably maintained in growing bacterial populations or when acquired by a new host after transfer; such mechanisms may well provide novel drug targets. The results will also lead to the development of improved methods for the characterisation of clinical strains and the monitoring of antibiotic resistance, and will be of broad relevance to the problem of antimicrobial resistance in bacterial pathogens. Most importantly, the application of knowledge arising from these studies to the design and implementation of rational antibiotic usage policies has the potential to extend the efficacy of existing and future anti-staphylococcal therapies.