Roy Monojit Kumar, Bhattacharjee Abhilash, Singh Anil Kumar
Center for Biotechnology, Biological Sciences, and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat, Assam, 785006, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 220002, India.
Arch Microbiol. 2025 Sep 16;207(11):263. doi: 10.1007/s00203-025-04465-2.
Antimicrobial resistance (AMR) is a major global health threat, mainly driven by the rapid spread of resistance genes through horizontal gene transfer (HGT). The Type IV Secretion System (T4SS) acts as a crucial molecular machinery that facilitates this process, allowing bacteria to transfer DNA, effector proteins, and virulence factors. This review systematically explores the structural and functional diversity of T4SS, its role in spreading AMR, and current methods for its inhibition. T4SS consists of a multi-protein complex that spans bacterial membranes, mediating conjugative plasmid transfer, host-pathogen interactions, and bacterial competition. Key components include ATPases, pilus structures, and membrane-associated proteins that show both conserved features and species-specific adaptations. These traits enable functional specialization across Gram-positive and Gram-negative bacteria, significantly contributing to the spread of vital resistance genes like extended-spectrum β-lactamases and carbapenemases via mobile genetic elements. Several approaches have been developed to inhibit T4SS and combat AMR. Small molecules targeting ATPase activity or protein interactions are promising, as are natural phytochemicals that interfere with conjugation. Bacteriophage therapy provides another strategy by specifically targeting plasmid-carrying bacteria. Host immune responses, such as innate immune recognition and secretory immunoglobulins, also show potential to influence T4SS activity. Although progress has been made, challenges remain, especially in developing selective inhibition methods that do not harm beneficial microbiota or host cells. Future research should focus on high-resolution structural studies to support rational drug design and preclinical testing of combination therapies that include T4SS inhibitors with existing antibiotics. Gaining a deeper understanding of T4SS regulation and host-pathogen interactions will be vital for creating targeted AMR strategies that also maintain ecological balance.
抗菌药物耐药性（AMR）是全球主要的健康威胁，主要由耐药基因通过水平基因转移（HGT）的快速传播驱动。IV型分泌系统（T4SS）是促进这一过程的关键分子机制，使细菌能够转移DNA、效应蛋白和毒力因子。本综述系统地探讨了T4SS的结构和功能多样性、其在AMR传播中的作用以及目前的抑制方法。T4SS由跨越细菌膜的多蛋白复合物组成，介导接合性质粒转移、宿主-病原体相互作用和细菌竞争。关键成分包括ATP酶、菌毛结构和膜相关蛋白，它们既具有保守特征，又有物种特异性适应性。这些特性使革兰氏阳性菌和革兰氏阴性菌具有功能特异性，通过移动遗传元件显著促进了超广谱β-内酰胺酶和碳青霉烯酶等重要耐药基因的传播。已经开发了几种方法来抑制T4SS并对抗AMR。靶向ATP酶活性或蛋白质相互作用的小分子很有前景，干扰接合作用的天然植物化学物质也是如此。噬菌体疗法通过特异性靶向携带质粒的细菌提供了另一种策略。宿主免疫反应，如先天免疫识别和分泌型免疫球蛋白，也显示出影响T4SS活性的潜力。尽管已经取得了进展，但挑战仍然存在，特别是在开发不损害有益微生物群或宿主细胞的选择性抑制方法方面。未来的研究应侧重于高分辨率结构研究，以支持合理的药物设计和包括T4SS抑制剂与现有抗生素的联合疗法的临床前测试。深入了解T4SS调控和宿主-病原体相互作用对于制定既能维持生态平衡又能靶向AMR的策略至关重要。
