School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, China.
Curr Med Chem. 2019;26(13):2297-2312. doi: 10.2174/0929867324666171121102829.
The increasing threats of antibiotic resistance urge the need for developing new approaches to combat bacterial infections including those caused by Staphylococcus aureus (S. aureus). Unlike conventional antibiotics that aim to kill bacteria or inhibit their growth, targeting bacterial virulence may be a promising alternative approach, which imposes less selective pressure for antibiotic resistance in future generations.
Our goal is to provide a systematic review about developing high-throughput screening (HTS) strategies for the identification of inhibitors targeting virulence of S. aureus. We also describe an overview of virulence regulatory pathways for potential antivirulence targets.
We focus on five potential targets or target families, including agr quorum sensing system, SarA/MgrA protein family, sortase A, Clp protease and eukaryotic-like Ser/Thr phosphatase (Stp1). For each target, we introduce its role in virulence regulation, summarize the HTS approaches that are used to identify novel anti-virulence inhibitors, and discuss the advantages and disadvantages of these strategies.
The discovery of anti-virulence inhibitors via HTS underlines the promising potential of anti-virulence therapy for S. aureus. The development of HTS strategies can facilitate the identification of novel anti-virulence inhibitors for combating S. aureus infection, and may also advance our understanding on virulence regulation in S. aureus.
抗生素耐药性的威胁不断增加，促使我们需要开发新的方法来对抗细菌感染，包括金黄色葡萄球菌（S. aureus）引起的感染。与旨在杀死细菌或抑制其生长的传统抗生素不同，靶向细菌毒力可能是一种有前途的替代方法，因为它在未来几代中对抗生素耐药性的选择性压力较小。
我们的目标是提供一个关于开发针对金黄色葡萄球菌毒力的抑制剂的高通量筛选（HTS）策略的系统评价。我们还描述了金黄色葡萄球菌毒力调控途径的概述，以寻找潜在的抗毒力靶标。
我们重点关注五个潜在的靶标或靶标家族，包括agr 群体感应系统、SarA/MgrA 蛋白家族、分选酶 A、Clp 蛋白酶和真核样丝氨酸/苏氨酸磷酸酶（Stp1）。对于每个靶标，我们介绍其在毒力调控中的作用，总结用于鉴定新型抗毒力抑制剂的 HTS 方法，并讨论这些策略的优缺点。
通过 HTS 发现抗毒力抑制剂突出了抗毒力疗法在金黄色葡萄球菌中的潜在前景。HTS 策略的发展可以促进新型抗毒力抑制剂的鉴定，以对抗金黄色葡萄球菌感染，并可能进一步加深我们对金黄色葡萄球菌毒力调控的理解。
