Maffioli Sonia I, Zhang Yu, Degen David, Carzaniga Thomas, Del Gatto Giancarlo, Serina Stefania, Monciardini Paolo, Mazzetti Carlo, Guglierame Paola, Candiani Gianpaolo, Chiriac Alina Iulia, Facchetti Giuseppe, Kaltofen Petra, Sahl Hans-Georg, Dehò Gianni, Donadio Stefano, Ebright Richard H
NAICONS Srl, 20139 Milan, Italy; Vicuron Pharmaceuticals, 21040 Gerenzano, Italy.
Waksman Institute and Department of Chemistry, Rutgers University, Piscataway, NJ 08854, USA.
Cell. 2017 Jun 15;169(7):1240-1248.e23. doi: 10.1016/j.cell.2017.05.042.
Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy.
耐药性细菌病原体构成了紧迫的公共卫生危机。在此，我们报告了从微生物提取物筛选中发现的一种核苷类似物抑制剂，它能抑制细菌RNA聚合酶（RNAP），并对耐药性细菌病原体表现出抗菌活性：假尿嘧啶霉素（PUM）。PUM是一种天然产物，由一个甲脒化的、N-羟基化的甘氨酰-谷氨酰胺二肽与6'-氨基-假尿嘧啶连接而成。PUM在体外能有效且选择性地抑制细菌RNAP，抑制培养物中的细菌生长，并在化脓性链球菌腹膜炎小鼠模型中清除感染。PUM通过RNAP上的一个结合位点（NTP添加位点）和一种机制（与UTP竞争占据NTP添加位点）抑制RNAP，这与RNAP抑制剂及当前抗菌药物利福平（Rif）的不同。与Rif联合使用时，PUM表现出相加抗菌活性，与Rif无交叉耐药性，且自发耐药率比Rif低一个数量级。PUM是抗菌治疗中极有前景的先导物。
