Anti-MRSA agent discovery using Caenorhabditis elegans -based high-throughput screening
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MINIREVIEW Anti-MRSA agent discovery using Caenorhabditis elegans-based high-throughput screening Soo Min Kim1, Iliana Escorbar2, Kiho Lee2, Beth Burgwyn Fuchs2, Eleftherios Mylonakis2, and Wooseong Kim1* 1
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea 2 Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island, 02903, USA (Received Mar 30, 2020 / Revised May 4, 2020 / Accepted May 6, 2020)
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. elegansbased screening strategy as a paradigm shift screening platform. Keywords: antibiotic resistance, MRSA, Caenorhabditis elegans, high throughput screening, bacterial persisters, antiinfectives, host-pathogen interaction
*For correspondence. E-mail: [email protected]; Tel.: +82-23277-3372; Fax: +82-2-3277-4526 Copyright G2020, The Microbiological Society of Korea
Introduction Staphylococcus aureus is a facultative anaerobic Gram-positive bacterium found in normal human flora. Approximately one third of the human population carries S. aureus on their skin and in mucosal membranes (Gordon and Lowy, 2008; Tong et al., 2015). S. aureus is typically benign; however, it can also turn into a notorious pathogen causing a broad range of illnesses, from minor skin infections and food poisoning to detrimental toxic shock syndrome, endocarditis, and osteomyelitis (Tong et al., 2015; Troeman et al., 2019). Since penicillin was introduced in the 1940s, several antibiotics, including vancomycin, linezolid, and daptomycin, have been developed. However, S. aureus remains one of the most common c
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