Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K. pneumoniae, Escherichia coli, and Salmonella TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniae tmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning.IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings-especially carbapenem-resistant K. pneumoniae Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a "One Health" perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

中文翻译：

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肺炎克雷伯氏菌中对多种药物（包括替加环素）具有抗药性的质粒编码抗药性-结节-分区外排泵的出现。

属于染色体编码的抗性结节分支（RND）超家族的转运蛋白介导了革兰氏阴性细菌的多重耐药性。然而，将编码RND型泵的大基因簇从染色体到质粒的共转移似乎很少，并且尚未发现质粒介导的RND外排泵基因簇可赋予对替加环素的抗性。在这里，我们从五个源于动物的耐Pandrugella肺炎克雷伯菌的质粒上鉴定了一个新型的RND外排泵基因簇，命名为tmexCD1-toprJ1。TMexCD1-TOprJ1与肺炎克雷伯菌，大肠杆菌和沙门氏菌的四环素（包括替加环素和艾拉环素），喹诺酮类，头孢菌素和氨基糖苷类的MIC升高（增加了4到32倍），TMexCD1-TOprJ1的MIC密切相关（相对于64.5％） 77。与铜绿假单胞菌染色体上编码的MexCD-OprJ外排泵有8％的氨基酸同一性）在IncFIA质粒pHNAH8I中，tmexCD1-toprJ1基因簇与编码位点特异性整合的两个基因相邻。它的收购。TMexCD1-TOprJ1在大肠杆菌中的表达导致替加环素外排增加，而在肺炎克雷伯菌中，在体内感染模型中，替加环素的功效无效。TMexCD1-TOprJ1的表达降低了大肠杆菌和沙门氏菌的生长，但肺炎克雷伯氏菌tmexCD1-toprJ1阳性肠杆菌科分离株在人类中很少见（0.08％），但在鸡粪（14.3％）和零售肉类（3.4％）中更常见）样品。质粒携带的tmexCD1-toprJ1样基因簇在GenBank的肠杆菌科细菌和假单胞菌菌株的序列中得到了鉴定。通过质粒进一步在肠杆菌科中进一步传播tmexCD1-toprJ1基因簇及其类似物的可能性可能是公共卫生规划的重要考虑因素。在一个日益增长的对抗菌素耐药性的关注的时代，替加环素可能起着至关重要的作用。在对碳青霉烯耐药的肠杆菌科的治疗中，这是人类临床环境中最成问题的病原体，尤其是对碳青霉烯耐药的肺炎克雷伯菌。从食用动物中分离出肺炎链球菌。tmexCD1-toprJ1似乎起源于假单胞菌物种的染色体，可能已通过邻近的位点特异性整合转移到质粒上。尽管tmexCD1-toprJ1在人类临床分离株中仍然很少见，但考虑到tmexCD1-toprJ1基因簇的可转移性和TMexCD1-TOprJ1的广泛底物谱，该移动的替加环素抗性决定簇可以进一步传播。因此，从“一个健康”的角度来看，迫切需要采取措施来监视和控制其进一步扩散。当前人类临床分离株的低流行为设计和实施应对措施提供了宝贵的时间窗口。尽管tmexCD1-toprJ1在人类临床分离株中仍然很少见，但考虑到tmexCD1-toprJ1基因簇的可转移性和TMexCD1-TOprJ1的广泛底物谱，该移动的替加环素抗性决定簇可以进一步传播。因此，从“一个健康”的角度来看，迫切需要采取措施来监视和控制其进一步扩散。当前人类临床分离株的低流行为设计和实施应对措施提供了宝贵的时间窗口。尽管tmexCD1-toprJ1在人类临床分离株中仍然很少见，但考虑到tmexCD1-toprJ1基因簇的可转移性和TMexCD1-TOprJ1的广泛底物谱，该移动的替加环素抗性决定簇可以进一步传播。因此，从“一个健康”的角度来看，迫切需要采取措施来监视和控制其进一步扩散。当前人类临床分离株的低流行为设计和实施应对措施提供了宝贵的时间窗口。因此，迫切需要采取措施来监测和控制其进一步扩散。当前人类临床分离株的低流行为设计和实施应对措施提供了宝贵的时间窗口。因此，迫切需要采取措施来监测和控制其进一步扩散。当前人类临床分离株的低流行为设计和实施应对措施提供了宝贵的时间窗口。