Foss Marie H, Hurley Katherine A, Sorto Nohemy, Lackner Laura L, Thornton Kelsey M, Shaw Jared T, Weibel Douglas B
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706.
ACS Med Chem Lett. 2011 Apr 14;2(4):289-292. doi: 10.1021/ml1002822.
This paper characterizes N-benzyl-3-sulfonamidopyrrolidines (gyramides) as DNA gyrase inhibitors. Gyramide A was previously shown to exhibit antimicrobial activity that suggested it inhibited bacterial cell division. In this study, we conducted target identification studies and identified DNA gyrase as the primary target of gyramide A. The gyramide A resistance-determining region in DNA gyrase is adjacent to the DNA cleavage gate and is a new site for inhibitor design. We studied the antibiotic effects of gyramides A-C in combination with the Gram-negative efflux pump inhibitor MC-207,110 (60 μM). The gyramides had a minimum inhibitory concentration of 10-40 μM against Escherichia coli, Pseudomonas aeruginosa, Salmonella enterica, Staphylococcus aureus, and Streptococcus pneumoniae; the compounds were ineffective against Enterococcus faecalis. The IC(50) of gyramides A-C against E. coli DNA gyrase was 0.7- 3.3 μM. The N-benzyl-3-sulfonamidopyrrolidines described in this manuscript represent a starting point for development of antibiotics that bind a new site in DNA gyrase.
本文将N-苄基-3-磺酰胺基吡咯烷（gyramides）表征为DNA促旋酶抑制剂。先前已表明Gyramide A具有抗菌活性，这表明它抑制细菌细胞分裂。在本研究中，我们进行了靶点鉴定研究，并确定DNA促旋酶是Gyramide A的主要靶点。DNA促旋酶中Gyramide A抗性决定区域与DNA切割门相邻，是抑制剂设计的新位点。我们研究了Gyramides A-C与革兰氏阴性菌外排泵抑制剂MC-207,110（60μM）联合使用的抗菌效果。Gyramides对大肠杆菌、铜绿假单胞菌、肠炎沙门氏菌、金黄色葡萄球菌和肺炎链球菌的最低抑菌浓度为10-40μM；这些化合物对粪肠球菌无效。Gyramides A-C对大肠杆菌DNA促旋酶的IC50为0.7-3.3μM。本手稿中描述的N-苄基-3-磺酰胺基吡咯烷代表了开发与DNA促旋酶新位点结合的抗生素的起点。
