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1.宁夏大学 生命科学学院, 宁夏 银川 750021
2.宁夏大学 新华学院, 宁夏 银川 750021
Received:18 May 2026,
Online First:13 July 2026,
Published:15 July 2026
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薛津晶,田丽芝,王丽,等.Tet(X)家族介导的四环素耐药性及其抑制剂的研究进展[J].宁夏大学学报(自然科学版中英文),2026,47(4):381-392.
Xue Jinjing,Tian Lizhi,Wang Li,et al.Research on Tet(X) Family-Mediated Tetracycline Resistance and Its Inhibitors[J].Journal of Ningxia University (Natural Science Edition in Chinese and English),2026,47(4):381-392.
薛津晶,田丽芝,王丽,等.Tet(X)家族介导的四环素耐药性及其抑制剂的研究进展[J].宁夏大学学报(自然科学版中英文),2026,47(4):381-392. DOI: 10.20176/j.cnki.nxdz.20260705.
Xue Jinjing,Tian Lizhi,Wang Li,et al.Research on Tet(X) Family-Mediated Tetracycline Resistance and Its Inhibitors[J].Journal of Ningxia University (Natural Science Edition in Chinese and English),2026,47(4):381-392. DOI: 10.20176/j.cnki.nxdz.20260705.
四环素类抗生素是临床治疗多重耐药革兰氏阴性菌感染的核心药物之一。替加环素作为第三代四环素类药物,是临床应对耐碳青霉烯肠杆菌科细菌(CRE)、多重耐药鲍曼不动杆菌(MDR-Ab)、耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)等多重耐药菌感染的“最后一道防线”。既往研究普遍认为,Tet(X)家族黄素依赖型单加氧酶仅存在于环境微生物中,且仅介导细菌对四环素类抗生素产生低水平耐药。然而2019年,我国科研团队首次发现了由质粒介导的四环素降解酶Tet(X3)和Tet(X4),二者可使革兰氏阴性菌对包括替加环素在内的所有四环素类抗生素产生高水平耐药。目前,Tet(X3)、Tet(X4)及其突变体已在全球快速扩散,临床菌株检出率逐年升高,极大削弱了四环素类药物的临床治疗效果,给临床抗感染诊疗及全球公共卫生安全带来严峻挑战。论文全面归纳总结了各类Tet(X)耐药酶的分子结构特征、催化机制、传播流行规律及其抑制剂的研究进展。同时剖析当前抑制剂研发面临的核心瓶颈,包括成药性差、靶点选择性低、体内药效不明确、临床转化进程滞后等问题,并从优化抑制剂分子结构优化、新型筛选技术开发等角度,系统展望该领域后续研究方向与耐药防控策略,以期为临床防控 Tet (X) 介导的四环素类耐药菌感染提供文献依据与研究思路。
Tetracyclines are among the key antimicrobial agents used clinically to treat infections caused by multidrug-resistant Gram-negative bacteria. Tigecycline, as a third-generation tetracycline, is considered a last-resort therapeutic option for severe infections caused by multidrug-resistant pathogens, including carbapenem-resistant
Enterobacterales
(CRE), multidrug-resistant
Acinetobacter baumannii
(MDR-Ab), methicillin-resistant
Staphylococcus aureus
(MRSA), and vancomycin-resistant
Enterococci
(VRE). Previous studies generally concluded that Tet (X) family flavin-dependent monooxygenases were restricted to environmental microorganisms and conferred only low-level resistance to tetracyclines. However, in 2019, a Chinese research team identified the plasmid-borne tetracycline-degrading enzymes Tet (X3) and Tet (X4) for the first time. These enzymes confer high-level resistance to all tetracycline antibiotics, including tigecycline, in Gram-negative bacteria. To date, Tet (X3), Tet (X4) and their variants have spread rapidly worldwide, and their detection rates in clinical isolates have increased annually. This development has substantially compromised the clinical efficacy of tetracyclines and poses severe challenges to clinical anti-infective management and global public health security. This review comprehensively summarizes the molecular structural characteristics, catalytic mechanisms, dissemination and epidemiological patterns of various Tet (X) resistance enzymes, as well as recent advances in the development of their inhibitors. It also analyzes the major bottlenecks currently hindering Tet (X) inhibitor development, including poor druggability, insufficient target selectivity, unclear
in vivo
efficacy and limi
ted progress toward clinical translation. Focusing on the structural optimization of inhibitor molecules and the development of novel screening technologies, this review future discusses future research directions and strategies for antimicrobial resistance prevention and control. It is expected to provide a useful literature basis and research framework for the clinical prevention and treatment of infections caused by Tet (X)-mediated tetracycline-resistant bacteria.
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