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Discovery and Optimization of nTZDpa as an Antibiotic Effective Against Bacterial Persisters
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-08-22 00:00:00 , DOI: 10.1021/acsinfecdis.8b00161 Wooseong Kim 1 , Andrew D. Steele 2 , Wenpeng Zhu 3 , Erika E. Csatary 2 , Nico Fricke 3 , Madeline M. Dekarske 2 , Elamparithi Jayamani 1 , Wen Pan 1 , Bumsup Kwon 4 , Isabelle F. Sinitsa 5 , Jake L. Rosen 2 , Annie L. Conery 6, 7 , Beth Burgwyn Fuchs 1 , Petia M. Vlahovska 8 , Frederick M. Ausubel 6, 7 , Huajian Gao 3 , William M. Wuest 2 , Eleftherios Mylonakis 1
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-08-22 00:00:00 , DOI: 10.1021/acsinfecdis.8b00161 Wooseong Kim 1 , Andrew D. Steele 2 , Wenpeng Zhu 3 , Erika E. Csatary 2 , Nico Fricke 3 , Madeline M. Dekarske 2 , Elamparithi Jayamani 1 , Wen Pan 1 , Bumsup Kwon 4 , Isabelle F. Sinitsa 5 , Jake L. Rosen 2 , Annie L. Conery 6, 7 , Beth Burgwyn Fuchs 1 , Petia M. Vlahovska 8 , Frederick M. Ausubel 6, 7 , Huajian Gao 3 , William M. Wuest 2 , Eleftherios Mylonakis 1
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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.
中文翻译：
发现和优化nTZDpa作为一种有效对抗细菌的抗生素
常规抗生素不能有效治疗由耐药性或持久性不生长细菌引起的感染，因此迫切需要开发新的抗生素。我们报告小分子nTZDpa，以前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，通过脂质双层破坏杀死生长和持久的金黄色葡萄球菌细胞。金黄色葡萄球菌表现出对nTZDpa的抗性没有可检测到的发展，并且该化合物与氨基糖苷类协同作用。通过利用分子动力学模拟指导的合成化学，与哺乳动物膜相比，我们提高了nTZDpa对MRSA膜的效价和选择性。这些研究为设计有效，有效对抗细菌持久性的选择性膜有效抗生素提供了重要的见识。
更新日期：2018-08-22
中文翻译：
发现和优化nTZDpa作为一种有效对抗细菌的抗生素
常规抗生素不能有效治疗由耐药性或持久性不生长细菌引起的感染，因此迫切需要开发新的抗生素。我们报告小分子nTZDpa，以前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，通过脂质双层破坏杀死生长和持久的金黄色葡萄球菌细胞。金黄色葡萄球菌表现出对nTZDpa的抗性没有可检测到的发展，并且该化合物与氨基糖苷类协同作用。通过利用分子动力学模拟指导的合成化学，与哺乳动物膜相比，我们提高了nTZDpa对MRSA膜的效价和选择性。这些研究为设计有效，有效对抗细菌持久性的选择性膜有效抗生素提供了重要的见识。
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