Sagong Hye Yeon, Rosado-Lugo Jesus D, Bryan Eric J, Ferrer-González Edgar, Wang Yiling, Cao Yanlu, Parhi Ajit K, Pilch Daniel S, LaVoie Edmond J
TAXIS Pharmaceuticals, Inc., Monmouth Junction, South Brunswick, NJ 08552, USA.
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Med Chem Res. 2022 Oct;31(10):1679-1704. doi: 10.1007/s00044-022-02967-y. Epub 2022 Sep 14.
MreB is a cytoskeleton protein present in rod-shaped bacteria that is both essential for bacterial cell division and highly conserved. Because most Gram (-) bacteria require MreB for cell division, chromosome segregation, cell wall morphogenesis, and cell polarity, it is an attractive target for antibacterial drug discovery. As MreB modulation is not associated with the activity of antibiotics in clinical use, acquired resistance to MreB inhibitors is also unlikely. Compounds, such as A22 and CBR-4830, are known to disrupt MreB function by inhibition of ATPase activity. However, the toxicity of these compounds has hindered efforts to assess the in vivo efficacy of these MreB inhibitors. The present study further examines the structure-activity of analogs related to CBR-4830 as it relates to relative antibiotic activity and improved drug properties. These data reveal that certain analogs have enhanced antibiotic activity. In addition, we evaluated several representative analogs (, , , , and ) for their abilities to target purified MreB (EcMreB) and inhibit its ATPase activity. Except for , all these analogs were more potent than CBR-4830 as inhibitors of the ATPase activity of EcMreB with corresponding IC values ranging from 6 ± 2 to 29 ± 9 μM.
MreB是一种存在于杆状细菌中的细胞骨架蛋白，对细菌细胞分裂至关重要且高度保守。由于大多数革兰氏阴性菌在细胞分裂、染色体分离、细胞壁形态发生和细胞极性方面都需要MreB，因此它是抗菌药物研发的一个有吸引力的靶点。由于MreB调节与临床使用的抗生素活性无关，因此对MreB抑制剂产生获得性耐药的可能性也不大。已知诸如A22和CBR - 4830等化合物可通过抑制ATP酶活性来破坏MreB功能。然而，这些化合物的毒性阻碍了评估这些MreB抑制剂体内疗效的努力。本研究进一步考察了与CBR - 4830相关的类似物的构效关系，及其与相对抗生素活性和改善药物特性的关联。这些数据表明某些类似物具有增强的抗生素活性。此外，我们评估了几种代表性类似物（、、、和）靶向纯化的MreB（EcMreB）并抑制其ATP酶活性的能力。除了之外，所有这些类似物作为EcMreB的ATP酶活性抑制剂都比CBR - 4830更有效，相应的IC值范围为6±2至29±9μM。
