Development of the computational antibiotic screening platform (CLASP) to aid in the discovery of new antibiotics
Development of the computational antibiotic screening platform (CLASP) to aid in the discovery of new antibiotics
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DOI：
10.1039/d0sm02035d
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发表时间：
2021-03-14
期刊：
影响因子：
3.4
通讯作者：
Nangia, Shikha
中科院分区：
文献类型：
--
作者：
Dai, Yinghui;Ma, Huilin;Nangia, Shikha
细菌在生物和非生物表面的定植以及抗生素耐药性是具有重要社会影响的重大挑战。然而，面对越来越多的细菌对所有已知抗生素的耐药性，发现新类别抗生素的努力已经停滞不前，迫切需要加快抗生素的发现管道。发现新抗生素的主要障碍是分子在细菌包膜上的渗透性有限。值得注意的是，革兰氏阴性菌具有营养特异性蛋白质通道（或孔蛋白），限制非必需分子（包括抗生素）的渗透性。在这里，我们开发了计算抗生素筛选平台（CLASP），用于筛选通过孔蛋白的潜在药物分子。CLASP利用粗粒度（CG）分辨率、先进的采样技术和并行计算环境来最大化其性能。CLASP可以在几个小时内获得潜在药物分子的全面热力学和动力学输出数据。它的输出包括平均力分布势、能垒、速率常数、分子与孔壁残基的接触分析以及分子在孔通道中的取向分析。在我们的第一个CLASP应用中，我们报告了六种碳青霉烯类抗生素（双青霉烯、多利培南、埃他培南、亚胺培南、美罗培南和帕尼培南）通过OccD3的运输特性，OccD3是铜绿假单胞菌摄取碳青霉烯的主要通道。CLASP旨在筛选周转时间短的小分子文库，以获得结构-性质关系，从而发现具有高通透性的抗生素。CLASP将免费分发，以加快抗生素药物的发现。
Bacterial colonization of biotic and abiotic surfaces and antibiotic resistance are grand challenges with paramount societal impacts. However, in the face of increasing bacterial resistance to all known antibiotics, efforts to discover new classes of antibiotics have languished, creating an urgent need to accelerate the antibiotic discovery pipeline. A major deterrent in the discovering of new antibiotics is the limited permeability of molecules across the bacterial envelope. Notably, the Gram-negative bacteria have nutrient specific protein channels (or porins) that restrict the permeability of non-essential molecules, including antibiotics. Here, we have developed the Computational Antibiotic Screening Platform (CLASP) for screening of potential drug molecules through the porins. The CLASP takes advantage of coarse grain (CG) resolution, advanced sampling techniques, and a parallel computing environment to maximize its performance. The CLASP yields comprehensive thermodynamic and kinetic output data of a potential drug molecule within a few hours of wall-clock time. Its output includes the potential of mean force profile, energy barrier, the rate constant, and contact analysis of the molecule with the pore-lining residues, and the orientational analysis of the molecule in the porin channel. In our first CLASP application, we report the transport properties of six carbapenem antibiotics-biapenem, doripenem, ertapenem, imipenem, meropenem, and panipenem-through OccD3, a major channel for carbapenem uptake in Pseudomonas aeruginosa. The CLASP is designed to screen small molecule libraries with a fast turnaround time to yield structure-property relationships to discover antibiotics with high permeability. The CLASP will be freely distributed to enable accelerated antibiotic drug discovery.