Zhu Jie, Cai Xiaoqing, Harris Tyler L, Gooyit Major, Wood Malcolm, Lardy Matthew, Janda Kim D
The Skaggs Institute for Chemical Biology and Departments of Chemistry and Immunology and the Worm Institute for Research and Medicine (WIRM), La Jolla, CA 92037, USA.
The Core Microscopy Facility, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chem Biol. 2015 Apr 23;22(4):483-491. doi: 10.1016/j.chembiol.2015.03.012. Epub 2015 Apr 16.
The emergence of antibiotic resistance places a sense of urgency on the development of alternative antibacterial strategies, of which targeting virulence factors has been regarded as a "second generation" antibiotic approach. In the case of Pseudomonas aeruginosa infections, a proteolytic virulence factor, LasB, is one such target. Unfortunately, we and others have not been successful in translating in vitro potency of LasB inhibitors to in vivo efficacy in an animal model. To overcome this obstacle, we now integrate in silico and in vitro identification of the mercaptoacetamide motif as an effective class of LasB inhibitors with full in vivo characterization of mercaptoacetamide prodrugs using Caenorhabditis elegans. We show that one of our mercaptoacetamide prodrugs has a good selectivity profile and high in vivo efficacy, and confirm that LasB is a promising target for the treatment of bacterial infections. In addition, our work highlights that the C. elegans infection model is a user-friendly and cost-effective translational tool for the development of anti-virulence compounds.
抗生素耐药性的出现使得开发替代抗菌策略变得紧迫，其中靶向毒力因子被视为一种“第二代”抗生素方法。就铜绿假单胞菌感染而言，一种蛋白水解毒力因子LasB就是这样一个靶点。不幸的是，我们和其他人都未能成功地将LasB抑制剂的体外效力转化为动物模型中的体内疗效。为了克服这一障碍，我们现在将巯基乙酰胺基序作为一类有效的LasB抑制剂的计算机模拟和体外鉴定与使用秀丽隐杆线虫对巯基乙酰胺前药进行全面的体内表征相结合。我们表明，我们的一种巯基乙酰胺前药具有良好的选择性谱和高体内疗效，并证实LasB是治疗细菌感染的一个有前景的靶点。此外，我们的工作强调，秀丽隐杆线虫感染模型是开发抗毒力化合物的一种用户友好且经济高效的转化工具。
