High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro

Abstract Clostridioides difficile is an enteric pathogen responsible for causing debilitating diarrhea, mostly in hospitalized patients. The bacterium exploits on microbial dysbiosis induced by the use of antibiotics to establish infection that ranges from mild watery diarrhea to pseudomembranous co...

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Autores principales:	Rusha Pal, Mingji Dai, Mohamed N. Seleem
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a361d52222ab4e87a199b8e5c805e5c5
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spelling	oai:doaj.org-article:a361d52222ab4e87a199b8e5c805e5c52021-12-02T15:49:45ZHigh-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro10.1038/s41598-021-90314-32045-2322https://doaj.org/article/a361d52222ab4e87a199b8e5c805e5c52021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90314-3https://doaj.org/toc/2045-2322Abstract Clostridioides difficile is an enteric pathogen responsible for causing debilitating diarrhea, mostly in hospitalized patients. The bacterium exploits on microbial dysbiosis induced by the use of antibiotics to establish infection that ranges from mild watery diarrhea to pseudomembranous colitis. The increased prevalence of the disease accompanied by exacerbated comorbidity and the paucity of anticlostridial drugs that can tackle recurrence entails novel therapeutic options. Here, we report new lead molecules with potent anticlostridial activity from the AnalytiCon NATx library featuring natural product-inspired or natural product-derived small molecules. A high-throughput whole-cell-based screening of 5000 synthetic compounds from the AnalytiCon NATx library helped us identify 10 compounds capable of inhibiting the pathogen. Out of these 10 hits, we found 3 compounds with potent activity against C. difficile (MIC = 0.5–2 μg/ml). Interestingly, these compounds had minimal to no effect on the indigenous intestinal microbial species tested, unlike the standard-of-care antibiotics vancomycin and fidaxomicin. Further in vitro investigation revealed that the compounds were nontoxic to Caco-2 cell line. Given their potent anticlostridial activity, natural product-inspired scaffolds may suggest potential avenues that can address the unmet needs in preventing C. difficile mediated disease.Rusha PalMingji DaiMohamed N. SeleemNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rusha Pal Mingji Dai Mohamed N. Seleem High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
description	Abstract Clostridioides difficile is an enteric pathogen responsible for causing debilitating diarrhea, mostly in hospitalized patients. The bacterium exploits on microbial dysbiosis induced by the use of antibiotics to establish infection that ranges from mild watery diarrhea to pseudomembranous colitis. The increased prevalence of the disease accompanied by exacerbated comorbidity and the paucity of anticlostridial drugs that can tackle recurrence entails novel therapeutic options. Here, we report new lead molecules with potent anticlostridial activity from the AnalytiCon NATx library featuring natural product-inspired or natural product-derived small molecules. A high-throughput whole-cell-based screening of 5000 synthetic compounds from the AnalytiCon NATx library helped us identify 10 compounds capable of inhibiting the pathogen. Out of these 10 hits, we found 3 compounds with potent activity against C. difficile (MIC = 0.5–2 μg/ml). Interestingly, these compounds had minimal to no effect on the indigenous intestinal microbial species tested, unlike the standard-of-care antibiotics vancomycin and fidaxomicin. Further in vitro investigation revealed that the compounds were nontoxic to Caco-2 cell line. Given their potent anticlostridial activity, natural product-inspired scaffolds may suggest potential avenues that can address the unmet needs in preventing C. difficile mediated disease.
format	article
author	Rusha Pal Mingji Dai Mohamed N. Seleem
author_facet	Rusha Pal Mingji Dai Mohamed N. Seleem
author_sort	Rusha Pal
title	High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
title_short	High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
title_full	High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
title_fullStr	High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
title_full_unstemmed	High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro
title_sort	high-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting clostridioides difficile in vitro
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a361d52222ab4e87a199b8e5c805e5c5
work_keys_str_mv	AT rushapal highthroughputscreeningidentifiesanovelnaturalproductinspiredscaffoldcapableofinhibitingclostridioidesdifficileinvitro AT mingjidai highthroughputscreeningidentifiesanovelnaturalproductinspiredscaffoldcapableofinhibitingclostridioidesdifficileinvitro AT mohamednseleem highthroughputscreeningidentifiesanovelnaturalproductinspiredscaffoldcapableofinhibitingclostridioidesdifficileinvitro
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High-throughput screening identifies a novel natural product-inspired scaffold capable of inhibiting Clostridioides difficile in vitro

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