Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
ACS Infect Dis. 2023 Apr 14;9(4):966-978. doi: 10.1021/acsinfecdis.2c00644. Epub 2023 Mar 15.
is found in the gut lining of more than half of the world's population, causes gastric ulcers, and contributes to stomach cancers. Menaquinone synthesis in relies on the rare futalosine pathway, where 5'-methylthioadenosine nucleosidase (MTAN) is proposed to play an essential role. Transition state analogues of MTAN, including BuT-DADMe-ImmA (BTDIA) and MeT-DADMe-ImmA (MTDIA), exhibit bacteriostatic action against numerous diverse clinical isolates of with minimum inhibitory concentrations (MIC's) of <2 ng/mL. Three BTDIA-resistant clones were selected under increasing BTDIA pressure. Whole genome sequencing showed no mutations in MTAN. Instead, resistant clones had mutations in , methionine adenosyltransferase (MAT), , a regulator of the iron transport system, and , a flagellar synthesis regulator. The mutation in causes expression of a MAT with increased catalytic activity, leading to elevated cellular -adenosylmethionine. Metabolite analysis and the mutations associated with resistance suggest multiple inputs associated with BTDIA resistance. Human gut microbiome exposed to MTDIA revealed no growth inhibition under aerobic or anaerobic conditions. Transition state analogues of MTAN have potential as agents for treating infection without disruption of the human gut microbiome or inducing resistance in the MTAN target.
丰原菌存在于全世界一半以上人口的肠道黏膜中，会导致胃溃疡，并促使胃癌发生。 依赖于罕见的 futalosine 途径合成甲萘醌，其中 5'-甲基硫代腺苷核苷酶（MTAN）被认为发挥着重要作用。MTAN 的过渡态类似物，包括 BuT-DADMe-ImmA（BTDIA）和 MeT-DADMe-ImmA（MTDIA），对多种不同临床分离株的 具有抑菌作用，最低抑菌浓度（MIC）<2ng/ml。在不断增加 BTDIA 压力下选择了 3 个 BTDIA 耐药克隆。全基因组测序未发现 MTAN 突变。相反，耐药克隆在 、甲硫氨酸腺苷转移酶（MAT）、铁转运系统调节剂 以及鞭毛合成调节剂 中发生突变。 中的突变导致表达具有更高催化活性的 MAT，从而导致细胞内 -腺苷甲硫氨酸水平升高。代谢物分析和与耐药相关的突变表明，BTDIA 耐药性与多种因素有关。在有氧或无氧条件下，暴露于 MTDIA 的人类肠道微生物组没有受到生长抑制。 MTAN 的过渡态类似物有可能成为治疗 感染的药物，而不会破坏人类肠道微生物组或在 MTAN 靶标中诱导耐药性。
