Wei Zilan, Xu Jie, Wu Jiahui, Wang Youliang, Chen Shuiping
Medical School of Chinese PLA, Beijing, China.
Department of Laboratory Medicine, 5th medical center of Chinese PLA General Hospital, Beijing, China.
Curr Microbiol. 2024 Dec 13;82(1):37. doi: 10.1007/s00284-024-04018-8.
Tigecycline is one of the last-resort treatment options for infections caused by carbapenem-resistant Klebsiella pneumoniae (KP). Unfortunately, tigecycline resistance is increasingly reported and causes an unprecedented public health crisis worldwide. Although studies on tigecycline resistance are expanding, the underlying mechanisms are not fully understood. The goal of this study is to investigate resistance-associated phenotypic changes in descendant tigecycline-resistant KP strains induced in vitro. Compared with the parental KP strains, descendant tigecycline-resistant strains grew slowly and reversed the susceptibility of carbapenems and aminoglycosides from resistance to sensitivity. The efflux pump inhibitor phenylalanyl-arginyl-β-naphthylamine (PAβN) could significantly decrease the MIC values of tigecycline in descendant strains, but the efflux pump inhibitor carbonyl cyanide-m-chlorophenylhydrazine (CCCP), verapamil, and reserpine could not. Although the descendant strains showed inconsistent (increased or decreased) biofilm formation and ethidium bromide uptake, they showed consistently decreased ethidium bromide efflux. As for the expression of efflux pumps and regulators determined by quantitative reverse transcript polymerase chain reaction (qRT-PCR), higher level of efflux pump acrAB-TolC and lower level of regulator ramA were observed in these descendant strains, while the efflux pump oqxAB and the other 6 regulators (acrR, rarA, marA, soxS, bpeT, and Rob) showed inconsistent (higher or lower) expression level. Thus, a global regulatory network driven by regulators (acrR, ramA, rarA, marA, soxS, bpeT, rob, etc.) alone or synergistically might play important roles in conferring tigecycline resistance in KP by regulation of efflux pumps (especially increasing acrAB-TolC) or other pathways.
替加环素是耐碳青霉烯类肺炎克雷伯菌（KP）引起的感染的最后治疗选择之一。不幸的是，替加环素耐药性的报道日益增多，并在全球范围内引发了前所未有的公共卫生危机。尽管关于替加环素耐药性的研究不断扩展，但其潜在机制尚未完全明确。本研究的目的是调查体外诱导产生的替加环素耐药KP后代菌株中与耐药相关的表型变化。与亲代KP菌株相比，替加环素耐药后代菌株生长缓慢，并使碳青霉烯类和氨基糖苷类药物的敏感性从耐药转变为敏感。外排泵抑制剂苯丙氨酰-精氨酰-β-萘胺（PAβN）可显著降低后代菌株中替加环素的最低抑菌浓度（MIC）值，但外排泵抑制剂羰基氰-m-氯苯腙（CCCP）、维拉帕米和利血平则不能。尽管后代菌株的生物膜形成和溴化乙锭摄取表现不一致（增加或减少），但它们的溴化乙锭外排始终减少。至于通过定量逆转录聚合酶链反应（qRT-PCR）测定的外排泵和调节子的表达，在这些后代菌株中观察到外排泵acrAB-TolC水平较高，调节子ramA水平较低，而外排泵oqxAB和其他6个调节子（acrR、rarA、marA、soxS、bpeT和Rob）的表达水平表现不一致（较高或较低）。因此，由调节子（acrR、ramA、rarA、marA、soxS、bpeT、rob等）单独或协同驱动的全局调控网络可能通过调节外排泵（尤其是增加acrAB-TolC）或其他途径在KP对替加环素耐药性的产生中发挥重要作用。
