Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Department of Cell and Molecular Biology, Uppsala University, Uppsala SE-75124, Sweden.
FEMS Microbiol Lett. 2024 Jan 9;371. doi: 10.1093/femsle/fnae084.
One of the debilitating causes of high mortality in the case of tuberculosis and other bacterial infections is the resistance development against standard drugs. There are limited studies so far to describe how a bacterial second messenger molecule can directly participate in distinctive antibiotic tolerance characteristics of a cell in a mechanism-dependent manner. Here we show that intracellular cyclic di-AMP (c-di-AMP) concentration can modulate drug sensitivity of Mycobacterium smegmatis by interacting with an effector protein or interfering with the 5'-UTR regions in mRNA of the genes and thus causing transcriptional downregulation of important genes in the pathways. We studied four antibiotics with different mechanisms of action: rifampicin, ciprofloxacin, erythromycin, and tobramycin and subsequently found that the level of drug sensitivity of the bacteria is directly proportional to the c-di-AMP concentration inside the cell. Further, we unraveled the underlying molecular mechanisms to delineate the specific genes and pathways regulated by c-di-AMP and hence result in differential drug sensitivity in M. smegmatis.
在结核病和其他细菌感染的高死亡率的诸多致病因素中，对标准药物产生耐药性是其中之一。到目前为止，关于细菌第二信使分子如何以依赖于机制的方式直接参与细胞中独特抗生素耐受性特征的研究还很有限。在这里，我们通过与效应蛋白相互作用或干扰基因 mRNA 的 5'UTR 区域来展示细胞内环二腺苷酸（c-di-AMP）浓度如何通过调节细胞内 c-di-AMP 浓度来调节耻垢分枝杆菌对药物的敏感性，从而导致途径中重要基因的转录下调。我们研究了四种具有不同作用机制的抗生素：利福平、环丙沙星、红霉素和妥布霉素，随后发现细菌的药物敏感性水平与细胞内的 c-di-AMP 浓度直接成正比。此外，我们还揭示了潜在的分子机制，以阐明 c-di-AMP 调节的特定基因和途径，从而导致耻垢分枝杆菌对药物的敏感性存在差异。
