Argonne National Laboratory, Argonne, IL 60439, USA.
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3531-6. doi: 10.1073/pnas.1217337110. Epub 2013 Feb 11.
The current epidemic of infections caused by antibiotic-resistant gram-positive bacteria requires the discovery of new drug targets and the development of new therapeutics. Lipoteichoic acid (LTA), a cell wall polymer of gram-positive bacteria, consists of 1,3-polyglycerol-phosphate linked to glycolipid. LTA synthase (LtaS) polymerizes polyglycerol-phosphate from phosphatidylglycerol, a reaction that is essential for the growth of gram-positive bacteria. We screened small molecule libraries for compounds inhibiting growth of Staphylococcus aureus but not of gram-negative bacteria. Compound 1771 [2-oxo-2-(5-phenyl-1,3,4-oxadiazol-2-ylamino)ethyl 2-naphtho[2,1-b]furan-1-ylacetate] blocked phosphatidylglycerol binding to LtaS and inhibited LTA synthesis in S. aureus and in Escherichia coli expressing ltaS. Compound 1771 inhibited the growth of antibiotic-resistant gram-positive bacteria and prolonged the survival of mice with lethal S. aureus challenge, validating LtaS as a target for the development of antibiotics.
当前抗生素耐药革兰阳性菌感染的流行需要发现新的药物靶点和开发新的治疗方法。革兰阳性菌的细胞壁聚合物脂磷壁酸（LTA）由 1,3-聚甘油磷酸与糖脂相连组成。LTA 合酶（LtaS）将磷脂酰甘油聚合生成多聚甘油磷酸，这是革兰阳性菌生长所必需的反应。我们筛选了小分子文库，以寻找抑制金黄色葡萄球菌生长而不抑制革兰氏阴性菌生长的化合物。化合物 1771 [2-氧代-2-（5-苯基-1,3,4-恶二唑-2-基氨基）乙基 2-萘[2,1-b]呋喃-1-基乙酸酯]阻止了磷脂酰甘油与 LtaS 的结合，并抑制了金黄色葡萄球菌和表达 ltaS 的大肠杆菌中的 LTA 合成。化合物 1771 抑制了耐药革兰氏阳性菌的生长，并延长了致命性金黄色葡萄球菌感染小鼠的存活时间，验证了 LtaS 作为开发抗生素的靶标。
