State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou, China.
Microbiol Spectr. 2024 Oct 3;12(10):e0397423. doi: 10.1128/spectrum.03974-23. Epub 2024 Aug 20.
The increasing clinical significance of is owed to its innate high-level, broad-spectrum resistance to antibiotics and therefore rapidly evolves as an important human pathogen. This warrants the identification of novel targets for aiding the discovery of new drugs or drug combinations to treat infections. This study is inspired by the drug-hypersensitive profile of a mutant (U14) with transposon insertion in . We validated the role of in intrinsic drug resistance in by constructing a selectable marker-free in-frame deletion in and complementing the mutant with the same or extended version of the gene and then followed by drug susceptibility testing. Judging by the putative function of MAB_1915, cell envelope permeability was studied by ethidium bromide accumulation assay and susceptibility testing against dyes and detergents. In this study, we established genetic evidence of the role of in intrinsic resistance to rifampicin, rifabutin, linezolid, clarithromycin, vancomycin, and bedaquiline. Disruption of has also been observed to cause a significant increase in cell envelope permeability in . Restoration of resistance is observed to depend on at least 27 base pairs upstream of the coding DNA sequence of . MAB_1915 could therefore be associated with cell envelope permeability, and hence its role in intrinsic resistance to multiple drugs in , which presents it as a novel target for future development of effective antimicrobials to overcome intrinsic drug resistance in .
This study reports the role of a putative fadD (MAB_1915) in innate resistance to multiple drugs by , hence identifying MAB_1915 as a valuable target and providing a baseline for further mechanistic studies and development of effective antimicrobials to check the high level of intrinsic resistance in this pathogen.
由于 固有高水平、广谱的抗生素耐药性，其临床意义日益增加，因此迅速成为一种重要的人类病原体。这就需要确定新的靶标，以帮助发现治疗 感染的新药或药物组合。本研究受突变体 （U14）中带有转座子插入 的药物敏感谱的启发。我们通过在 中构建无选择标记的框内缺失突变体，并通过相同或扩展版本的基因对突变体进行互补，然后进行药物敏感性测试，验证了 在固有药物耐药性中的作用。根据 MAB_1915 的假定功能，通过溴化乙锭积累测定法和对染料和去污剂的敏感性测试来研究细胞包膜通透性。在这项研究中，我们建立了 参与固有耐利福平、利福布丁、利奈唑胺、克拉霉素、万古霉素和贝达喹啉的遗传证据。还观察到破坏 会导致 细胞包膜通透性显著增加。观察到恢复耐药性取决于编码 DNA 序列上游至少 27 个碱基对。因此，MAB_1915 可能与细胞包膜通透性有关，从而在 固有耐多药中发挥作用，这使其成为未来开发有效抗菌药物以克服 固有药物耐药性的新靶标。
本研究报告了一个假定的 fadD（MAB_1915）在 固有耐药性中的作用，从而确定了 MAB_1915 作为一个有价值的靶标，并为进一步的机制研究和开发有效抗菌药物提供了基线，以检查该病原体的高水平固有耐药性。
