Staphylococcus aureus is a leading cause of hospital- and community-acquired infections. Despite current advances in antimicrobial chemotherapy, the infections caused by S. aureus remain challenging due to their ability to readily develop resistance. Indeed, antibiotic resistance, exemplified by methicillin-resistant S. aureus (MRSA) is a top threat to global health security. Furthermore, the current rate of antibiotic discovery is much slower than the rate of antibiotic-resistance development. It seems evident that the conventional in vitro bacterial growth-based screening strategies can no longer effectively supply new antibiotics at the rate needed to combat bacterial antibiotic-resistance. To overcome this antibiotic resistance crisis, screening assays based on host–pathogen interactions have been developed. In particular, the free-living nematode Caenorhabditis elegans has been used for drug screening against MRSA. In this review, we will discuss the general principles of the C. elegans-based screening platform and will highlight its unique strengths by comparing it with conventional antibiotic screening platforms. We will outline major hits from high-throughput screens of more than 100,000 small molecules using the C. elegans–MRSA infection assay and will review the mode-of-action of the identified hit compounds. Lastly, we will discuss the potential of a C. elegans-based screening strategy as a paradigm shift screening platform.

中文翻译：

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使用基于秀丽隐杆线虫的高通量筛选发现抗 MRSA 药物。

金黄色葡萄球菌是医院和社区获得性感染的主要原因。尽管目前在抗菌化学疗法方面取得了进展，但金黄色葡萄球菌引起的感染仍然具有挑战性，因为它们很容易产生耐药性。事实上，以耐甲氧西林金黄色葡萄球菌(MRSA)为例的抗生素耐药性是对全球卫生安全的最大威胁。此外，目前抗生素的发现速度远低于抗生素耐药性的发展速度。很明显，传统的体外基于细菌生长的筛选策略不再能够以对抗细菌抗生素耐药性所需的速度有效地提供新抗生素。为了克服这种抗生素耐药性危机，已经开发了基于宿主-病原体相互作用的筛选分析。特别是，自由生活的线虫秀丽隐杆线虫已被用于针对 MRSA 的药物筛选。在这篇综述中，我们将讨论基于线虫的筛选平台的一般原则，并将通过与传统抗生素筛选平台的比较来突出其独特的优势。我们将概述使用秀丽隐杆线虫对超过 100,000 个小分子进行高通量筛选的主要结果–MRSA 感染检测，并将审查已识别的命中化合物的作用方式。最后，我们将讨论基于线虫的筛选策略作为范式转换筛选平台的潜力。