Center for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
Curr Pharm Des. 2011;17(13):1291-302. doi: 10.2174/138161211795703726.
Traditional antimicrobials are increasingly suffering from the emergence of multidrug resistance among pathogenic microorganisms. To overcome these deficiencies, a range of novel approaches to control microbial infections are under investigation as potential alternative treatments. Multidrug efflux is a key target of these efforts. Efflux mechanisms are broadly recognized as major components of resistance to many classes of chemotherapeutic agents as well as antimicrobials. Efflux occurs due to the activity of membrane transporter proteins widely known as Multidrug Efflux Systems (MES). They are implicated in a variety of physiological roles other than efflux and identifying natural substrates and inhibitors is an active and expanding research discipline. One plausible alternative is the combination of conventional antimicrobial agents/antibiotics with small molecules that block MES known as multidrug efflux pump inhibitors (EPIs). An array of approaches in academic and industrial research settings, varying from high-throughput screening (HTS) ventures to bioassay guided purification and determination, have yielded a number of promising EPIs in a series of pathogenic systems. This synergistic discovery platform has been exploited in translational directions beyond the potentiation of conventional antimicrobial treatments. This venture attempts to highlight different tactical elements of this platform, identifying the need for highly informative and comprehensive EPI-discovery strategies. Advances in assay development genomics, proteomics as well as the accumulation of bioactivity and structural information regarding MES facilitates the basis for a new discovery era. This platform is expanding drastically. A combination of chemogenomics and chemoinformatics approaches will integrate data mining with virtual and physical HTS ventures and populate the chemical-biological interface with a plethora of novel chemotypes. This comprehensive step will expedite the preclinical development of lead EPIs.
传统的抗菌药物越来越受到致病微生物多药耐药性的影响。为了克服这些不足，人们正在研究一系列新的方法来控制微生物感染，作为潜在的替代治疗方法。多药外排是这些努力的一个关键目标。外排机制被广泛认为是许多类化疗药物和抗菌药物耐药的主要组成部分。由于广泛称为多药外排系统（MES）的膜转运蛋白的活性，外排发生。它们除了外排之外，还参与多种生理作用，并且鉴定天然底物和抑制剂是一个活跃且不断扩展的研究领域。一种合理的替代方法是将传统抗菌药物/抗生素与阻断 MES 的小分子（称为多药外排泵抑制剂（EPIs））联合使用。学术和工业研究环境中的一系列方法，从高通量筛选（HTS）风险投资到基于生物测定的纯化和测定，已经在一系列致病系统中产生了许多有前途的 EPI。这个协同发现平台已经在超越传统抗菌治疗增效的转化方向上得到了利用。这项工作试图突出这个平台的不同策略要素，确定需要高度信息丰富和全面的 EPI 发现策略。在测定发展、基因组学、蛋白质组学方面的进展，以及关于 MES 的生物活性和结构信息的积累，为新的发现时代奠定了基础。这个平台正在迅速扩大。化学基因组学和化学信息学方法的结合将数据挖掘与虚拟和物理 HTS 风险投资相结合，并利用大量新型化学型填充化学 - 生物学界面。这个全面的步骤将加快先导 EPI 的临床前开发。
