Sun Shijun, Zhou Chaoe, Li Haijun, Sun Liying, Qi Saiqi, Liu Xinmin, Wang Wanhai
Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Geriatrics, Peking University First Hospital, Beijing, China.
Front Microbiol. 2025 Jun 17;16:1543470. doi: 10.3389/fmicb.2025.1543470. eCollection 2025.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical global public health challenge due to its significant association with morbidity and mortality. Ceftazidime-avibactam (CZA) has emerged as an effective therapy against CRKP producing the serine carbapenemase KPC; however, resistance driven by novel KPC variants is increasingly reported.
In this study, 27 CRKP isolates were collected from elderly pneumonia patients in China. Sequential isolates from a single patient undergoing prolonged hospitalization revealed dynamic resistance evolution.
Whole-genome sequencing identified KPC-227, a novel KPC variant, alongside the previously reported KPC-204. KPC-204, carrying a "DDK" insertion at position 270, conferred resistance to both carbapenems and CZA, while KPC-227, harboring a D179Y mutation, restored carbapenem susceptibility but maintained CZA resistance. Molecular docking analyses revealed that the D179Y mutation impaired meropenem hydrolysis by decreasing binding affinity. Additionally, colistin resistance was observed due to a novel mgrB mutation.
These findings highlight the high evolutionary potential of KPC enzymes and the importance of vigilance to curb the emergence and dissemination of resistance, which threatens the efficacy of critical lastresort antibiotics.
耐碳青霉烯类肺炎克雷伯菌（CRKP）因其与发病率和死亡率显著相关，成为全球公共卫生面临的一项严峻挑战。头孢他啶-阿维巴坦（CZA）已成为治疗产丝氨酸碳青霉烯酶KPC的CRKP的有效疗法；然而，由新型KPC变体导致的耐药性报道日益增多。
在本研究中，从中国老年肺炎患者中收集了27株CRKP分离株。对一名长期住院患者的连续分离株进行分析，揭示了耐药性的动态演变。
全基因组测序鉴定出一种新型KPC变体KPC-227以及先前报道的KPC-204。KPC-204在第270位携带“DDK”插入，对碳青霉烯类和CZA均耐药，而携带D179Y突变的KPC-227恢复了对碳青霉烯类的敏感性，但仍对CZA耐药。分子对接分析表明，D179Y突变通过降低结合亲和力损害了美罗培南的水解。此外，由于一种新型mgrB突变，观察到了对黏菌素的耐药性。
这些发现凸显了KPC酶的高进化潜力以及警惕以遏制耐药性的出现和传播的重要性，耐药性威胁到关键的最后一线抗生素的疗效。
