A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants

ABSTRACT Drug repurposing offers an expedited and economical route to develop new clinical therapeutics in comparison to traditional drug development. Growth-based high-throughput screening is concomitant with drug repurposing and enables rapid identification of new therapeutic uses for investigated...

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Auteurs principaux:	Ryan P. Trombetta, Paul M. Dunman, Edward M. Schwarz, Stephen L. Kates, Hani A. Awad
Format:	article
Langue:	EN
Publié:	American Society for Microbiology 2018
Sujets:	Staphylococcus aureus small-colony variants high-throughput screen drug repurposing chronic infection Microbiology QR1-502
Accès en ligne:	https://doaj.org/article/1e0a50069cf744c4848bf014e566bb50
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spelling	oai:doaj.org-article:1e0a50069cf744c4848bf014e566bb502021-11-15T15:22:26ZA High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants10.1128/mSphere.00422-182379-5042https://doaj.org/article/1e0a50069cf744c4848bf014e566bb502018-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00422-18https://doaj.org/toc/2379-5042ABSTRACT Drug repurposing offers an expedited and economical route to develop new clinical therapeutics in comparison to traditional drug development. Growth-based high-throughput screening is concomitant with drug repurposing and enables rapid identification of new therapeutic uses for investigated drugs; however, this traditional method is not compatible with microorganisms with abnormal growth patterns such as Staphylococcus aureus small-colony variants (SCV). SCV subpopulations are auxotrophic for key compounds in biosynthetic pathways, which result in low growth rate. SCV formation is also associated with reduced antibiotic susceptibility, and the SCV’s ability to revert to the normal cell growth state is thought to contribute to recurrence of S. aureus infections. Thus, there is a critical need to identify antimicrobial agents that are potent against SCV in order to effectively treat chronic infections. Accordingly, here we describe adapting an adenylate kinase (AK)-based cell death reporter assay to identify members of a Food and Drug Administration (FDA)-approved drug library that display bactericidal activity against S. aureus SCV. Four library members, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, exhibited potent SCV bactericidal activity against a stable S. aureus SCV. Further investigation showed that sitafloxacin was potent against methicillin-susceptible and -resistant S. aureus, as well as S. aureus within an established biofilm. Taken together, these results demonstrate the ability to use the AK assay to screen small-molecule libraries for SCV bactericidal agents and highlight the therapeutic potential of sitafloxacin to be repurposed to treat chronic S. aureus infections associated with SCV and/or biofilm growth states. IMPORTANCE Conventional antibiotics fail to successfully treat chronic osteomyelitis, endocarditis, and device-related and airway infections. These recurring infections are associated with the emergence of SCV, which are recalcitrant to conventional antibiotics. Studies have investigated antibiotic therapies to treat SCV-related infections but have had little success, emphasizing the need to identify novel antimicrobial drugs. However, drug discovery is a costly and time-consuming process. An alternative strategy is drug repurposing, which could identify FDA-approved and well-characterized drugs that could have off-label utility in treating SCV. In this study, we adapted a high-throughput AK-based assay to identify 4 FDA-approved drugs, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, which display antimicrobial activity against S. aureus SCV, suggesting an avenue for drug repurposing in order to effectively treat SCV-related infections. Additionally, this screening paradigm can easily be adapted for other drug/chemical libraries to identify compounds bactericidal against SCV.Ryan P. TrombettaPaul M. DunmanEdward M. SchwarzStephen L. KatesHani A. AwadAmerican Society for MicrobiologyarticleStaphylococcus aureussmall-colony variantshigh-throughput screendrug repurposingchronic infectionMicrobiologyQR1-502ENmSphere, Vol 3, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus small-colony variants high-throughput screen drug repurposing chronic infection Microbiology QR1-502
spellingShingle	Staphylococcus aureus small-colony variants high-throughput screen drug repurposing chronic infection Microbiology QR1-502 Ryan P. Trombetta Paul M. Dunman Edward M. Schwarz Stephen L. Kates Hani A. Awad A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
description	ABSTRACT Drug repurposing offers an expedited and economical route to develop new clinical therapeutics in comparison to traditional drug development. Growth-based high-throughput screening is concomitant with drug repurposing and enables rapid identification of new therapeutic uses for investigated drugs; however, this traditional method is not compatible with microorganisms with abnormal growth patterns such as Staphylococcus aureus small-colony variants (SCV). SCV subpopulations are auxotrophic for key compounds in biosynthetic pathways, which result in low growth rate. SCV formation is also associated with reduced antibiotic susceptibility, and the SCV’s ability to revert to the normal cell growth state is thought to contribute to recurrence of S. aureus infections. Thus, there is a critical need to identify antimicrobial agents that are potent against SCV in order to effectively treat chronic infections. Accordingly, here we describe adapting an adenylate kinase (AK)-based cell death reporter assay to identify members of a Food and Drug Administration (FDA)-approved drug library that display bactericidal activity against S. aureus SCV. Four library members, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, exhibited potent SCV bactericidal activity against a stable S. aureus SCV. Further investigation showed that sitafloxacin was potent against methicillin-susceptible and -resistant S. aureus, as well as S. aureus within an established biofilm. Taken together, these results demonstrate the ability to use the AK assay to screen small-molecule libraries for SCV bactericidal agents and highlight the therapeutic potential of sitafloxacin to be repurposed to treat chronic S. aureus infections associated with SCV and/or biofilm growth states. IMPORTANCE Conventional antibiotics fail to successfully treat chronic osteomyelitis, endocarditis, and device-related and airway infections. These recurring infections are associated with the emergence of SCV, which are recalcitrant to conventional antibiotics. Studies have investigated antibiotic therapies to treat SCV-related infections but have had little success, emphasizing the need to identify novel antimicrobial drugs. However, drug discovery is a costly and time-consuming process. An alternative strategy is drug repurposing, which could identify FDA-approved and well-characterized drugs that could have off-label utility in treating SCV. In this study, we adapted a high-throughput AK-based assay to identify 4 FDA-approved drugs, daunorubicin, ketoconazole, rifapentine, and sitafloxacin, which display antimicrobial activity against S. aureus SCV, suggesting an avenue for drug repurposing in order to effectively treat SCV-related infections. Additionally, this screening paradigm can easily be adapted for other drug/chemical libraries to identify compounds bactericidal against SCV.
format	article
author	Ryan P. Trombetta Paul M. Dunman Edward M. Schwarz Stephen L. Kates Hani A. Awad
author_facet	Ryan P. Trombetta Paul M. Dunman Edward M. Schwarz Stephen L. Kates Hani A. Awad
author_sort	Ryan P. Trombetta
title	A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
title_short	A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
title_full	A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
title_fullStr	A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
title_full_unstemmed	A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants
title_sort	high-throughput screening approach to repurpose fda-approved drugs for bactericidal applications against <named-content content-type="genus-species">staphylococcus aureus</named-content> small-colony variants
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/1e0a50069cf744c4848bf014e566bb50
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A High-Throughput Screening Approach To Repurpose FDA-Approved Drugs for Bactericidal Applications against <named-content content-type="genus-species">Staphylococcus aureus</named-content> Small-Colony Variants

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