鲍曼不动杆菌主要抗菌药物耐药机制研究

Acinetobacter baumannii has emerged as the most significant "superbug" causing nosocomial infections, and the increasing incidence of multidrug-resistant even pandrug-resistant isolates has resulted in quite difficulty in clinical anti-infection treatment. Currently, the main antimicrobial agents for the treatment of multidrug resistant A. baumannii infection are carbapenems, tigecycline, polymyxins and sulbactam. However, the resistance rates of the four classes of antimicrobial agents have been increasing in recent years, and the mechanisms is still unclear. The applicant has focused on the resistant mechanism of A. baumannii for many years. We accomplished the whole-genome sequencing of A. baumannii ZJ06, and have collected 2430 A. baumannii clinical isolates and acquired clinical resistant strains and/or induced resistant strains against the active four classes of antimicrobial agents. On the basis of these researches, we further plan to research the resistant mechanism, resistant islands and mobile elements in A. baumannii by high-throughput sequencing, comparative genome/transcriptome/proteome, and gene knockout experiments. The study will demonstrated the main resistant mechanism of the four classes of antimicrobial agents, reveal the special mechanism and key genes of antimicrobial agents resistance. The study will also play an important role in reducing the resistance development of A. baumannii, and will be helpful in the development of new antimicrobial agents.

鲍曼不动杆菌已成为院内感染最重要的"超级细菌"，多重耐药甚至全耐药菌株感染的不断增加，给临床抗感染治疗带来了极大困难。目前治疗多重耐药鲍曼不动杆菌感染的主要抗菌药物是碳青霉烯类抗生素、替加环素、多粘菌素和含舒巴坦制剂，近年来这四类药物的耐药率快速上升，其机制尚不明确。申请人长期致力于鲍曼不动杆菌耐药机制研究，完成了鲍曼不动杆菌ZJ06全基因组测序，已收集2430株鲍曼不动杆菌临床菌株，并获得了上述四种抗菌药物的临床耐药株和/或实验室诱导耐药株。本研究拟在此基础上，采用高通量测序、比较基因/转录/蛋白质组学及基因敲除等技术手段，对鲍曼不动杆菌的耐药机制、耐药岛及可移动基因元件进行深入研究，阐明其对上述四种抗菌药物的主要耐药机制及关键耐药基因，揭示鲍曼不动杆菌快速产生耐药的独特机制,对于减缓鲍曼不动杆菌耐药性的发展及耐药菌株感染的治疗有重要作用，并极可能为新抗菌药物的开发提供新思路。

鲍曼不动杆菌已成为院内感染最重要的“超级细菌”，多重耐药甚至全耐药菌株感染的不断增加，给临床抗感染治疗带来了极大困难。目前治疗多重耐药鲍曼不动杆菌感染的主要抗菌药物是碳青霉烯类抗生素、替加环素、多粘菌素和含舒巴坦制剂，近年来这四类药物的耐药率快速上升，其机制尚不明确。我们积极探索我国鲍曼不动杆菌碳青霉烯类抗生素耐药机制，替加环素耐药机制，多粘菌素耐药机制，舒巴坦耐药机制以及鲍曼不动杆菌体内进化机制。我们发现了1个新blaOXA同源基因，同时阐明了我国碳青霉烯耐药鲍曼不动杆菌blaOXA-23、 blaOXA-24 、blaOXA-58型碳青霉烯酶传播机制，也发现blaOXA-23的多拷贝机制及其对碳青霉烯类抗生素耐药的贡献，这进一步加深了我们对碳青霉烯类耐药机制的认识。我们探究了鲍曼不动杆菌替加环素耐药新机制（trm和plsC）及与不同种类抗菌药物固有耐药有关的蛋白AbrP，同时发现多粘菌素耐药相关基因lpxD::ISAba1以及补偿突变与多粘菌素耐药的鲍曼不动杆菌的产生和传播过程有关，明确了blaTEM-1基因的多拷贝极有可能是舒巴坦耐药的新机制，而这些治疗多重耐药鲍曼不动杆菌感染的主要抗菌药物的耐药机制的发现将有利于减缓鲍曼不动杆菌耐药性的发展，对耐药菌株感染的治疗有重要作用。最后，我们阐明了鲍曼不动杆菌在体内将朝ICL-2、耐药和黏液型方向进化，明确了鲍曼不动杆菌未来进化方向，也提示着我们未来需要关注的方向。