Kim Wooseong, Steele Andrew D, Zhu Wenpeng, Csatary Erika E, Fricke Nico, Dekarske Madeline M, Jayamani Elamparithi, Pan Wen, Kwon Bumsup, Sinitsa Isabelle F, Rosen Jake L, Conery Annie L, Fuchs Beth Burgwyn, Vlahovska Petia M, Ausubel Frederick M, Gao Huajian, Wuest William M, Mylonakis Eleftherios
Division of Infectious Diseases , Rhode Island Hospital and Warren Alpert Medical School of Brown University , 593 Eddy Street , Providence , Rhode Island 02903 , United States.
Department of Chemistry and Emory Antibiotic Resistance Center , Emory University , 1515 Dickey Drive , Atlanta , Georgia 30322 , United States.
ACS Infect Dis. 2018 Nov 9;4(11):1540-1545. doi: 10.1021/acsinfecdis.8b00161. Epub 2018 Aug 28.
Conventional antibiotics are not effective in treating infections caused by drug-resistant or persistent nongrowing bacteria, creating a dire need for the development of new antibiotics. We report that the small molecule nTZDpa, previously characterized as a nonthiazolidinedione peroxisome proliferator-activated receptor gamma partial agonist, kills both growing and persistent Staphylococcus aureus cells by lipid bilayer disruption. S. aureus exhibited no detectable development of resistance to nTZDpa, and the compound acted synergistically with aminoglycosides. We improved both the potency and selectivity of nTZDpa against MRSA membranes compared to mammalian membranes by leveraging synthetic chemistry guided by molecular dynamics simulations. These studies provide key insights into the design of selective and potent membrane-active antibiotics effective against bacterial persisters.
传统抗生素在治疗由耐药或持续不生长细菌引起的感染方面无效，这迫切需要开发新的抗生素。我们报告称，小分子nTZDpa（先前被表征为非噻唑烷二酮过氧化物酶体增殖物激活受体γ部分激动剂）通过破坏脂质双层杀死生长中的和持续存在的金黄色葡萄球菌细胞。金黄色葡萄球菌对nTZDpa未表现出可检测到的耐药性发展，并且该化合物与氨基糖苷类药物协同作用。通过利用分子动力学模拟指导的合成化学，我们提高了nTZDpa相对于哺乳动物膜对耐甲氧西林金黄色葡萄球菌（MRSA）膜的效力和选择性。这些研究为设计针对细菌持留菌有效的选择性和强效膜活性抗生素提供了关键见解。
