Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets

The activity profile of a protein tyrosine phosphatase (PTP) inhibitor and redox thiol oxidant, nitropropenyl benzodioxole (NPBD), was investigated across a broad range of bacterial species. In vitro assays assessed inhibitory and lethal activity patterns, the induction of drug variants on long term...

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Autores principales:	Kylie White, Gina Nicoletti, Hugh Cornell
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antimicrobial nitropropenyl benzodioxole nitroalkenyl benzenes tyrosine signaling protein tyrosine phosphatase inhibitor thiol oxidant Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/e078e9d8eb0e40d2abacfbbd2a4a005c
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spelling	oai:doaj.org-article:e078e9d8eb0e40d2abacfbbd2a4a005c2021-11-25T16:22:34ZAntibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets10.3390/antibiotics101113102079-6382https://doaj.org/article/e078e9d8eb0e40d2abacfbbd2a4a005c2021-10-01T00:00:00Zhttps://www.mdpi.com/2079-6382/10/11/1310https://doaj.org/toc/2079-6382The activity profile of a protein tyrosine phosphatase (PTP) inhibitor and redox thiol oxidant, nitropropenyl benzodioxole (NPBD), was investigated across a broad range of bacterial species. In vitro assays assessed inhibitory and lethal activity patterns, the induction of drug variants on long term exposure, the inhibitory interactions of NPBD with antibiotics, and the effect of plasma proteins and redox thiols on activity. A literature review indicates the complexity of PTP and redox signaling and suggests likely metabolic targets. NPBD was broadly bactericidal to pathogens of the skin, respiratory, urogenital and intestinal tracts. It was effective against antibiotic resistant strains and slowly replicating and dormant cells. NPBD did not induce resistant or drug-tolerant phenotypes and showed low cross reactivity with antibiotics in synergy assays. Binding to plasma proteins indicated lowered in-vitro bioavailability and reduction of bactericidal activity in the presence of thiols confirmed the contribution of thiol oxidation and oxidative stress to lethality. This report presents a broad evaluation of the antibacterial effect of PTP inhibition and redox thiol oxidation, illustrates the functional diversity of bacterial PTPs and redox thiols, and supports their consideration as novel targets for antimicrobial drug development. NPBD is a dual mechanism agent with an activity profile which supports consideration of tyrosine phosphatases and bacterial antioxidant systems as promising targets for drug development.Kylie WhiteGina NicolettiHugh CornellMDPI AGarticleantimicrobialnitropropenyl benzodioxolenitroalkenyl benzenestyrosine signalingprotein tyrosine phosphatase inhibitorthiol oxidantTherapeutics. PharmacologyRM1-950ENAntibiotics, Vol 10, Iss 1310, p 1310 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial nitropropenyl benzodioxole nitroalkenyl benzenes tyrosine signaling protein tyrosine phosphatase inhibitor thiol oxidant Therapeutics. Pharmacology RM1-950
spellingShingle	antimicrobial nitropropenyl benzodioxole nitroalkenyl benzenes tyrosine signaling protein tyrosine phosphatase inhibitor thiol oxidant Therapeutics. Pharmacology RM1-950 Kylie White Gina Nicoletti Hugh Cornell Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
description	The activity profile of a protein tyrosine phosphatase (PTP) inhibitor and redox thiol oxidant, nitropropenyl benzodioxole (NPBD), was investigated across a broad range of bacterial species. In vitro assays assessed inhibitory and lethal activity patterns, the induction of drug variants on long term exposure, the inhibitory interactions of NPBD with antibiotics, and the effect of plasma proteins and redox thiols on activity. A literature review indicates the complexity of PTP and redox signaling and suggests likely metabolic targets. NPBD was broadly bactericidal to pathogens of the skin, respiratory, urogenital and intestinal tracts. It was effective against antibiotic resistant strains and slowly replicating and dormant cells. NPBD did not induce resistant or drug-tolerant phenotypes and showed low cross reactivity with antibiotics in synergy assays. Binding to plasma proteins indicated lowered in-vitro bioavailability and reduction of bactericidal activity in the presence of thiols confirmed the contribution of thiol oxidation and oxidative stress to lethality. This report presents a broad evaluation of the antibacterial effect of PTP inhibition and redox thiol oxidation, illustrates the functional diversity of bacterial PTPs and redox thiols, and supports their consideration as novel targets for antimicrobial drug development. NPBD is a dual mechanism agent with an activity profile which supports consideration of tyrosine phosphatases and bacterial antioxidant systems as promising targets for drug development.
format	article
author	Kylie White Gina Nicoletti Hugh Cornell
author_facet	Kylie White Gina Nicoletti Hugh Cornell
author_sort	Kylie White
title	Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
title_short	Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
title_full	Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
title_fullStr	Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
title_full_unstemmed	Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets
title_sort	antibacterial profile of a microbicidal agent targeting tyrosine phosphatases and redox thiols, novel drug targets
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e078e9d8eb0e40d2abacfbbd2a4a005c
work_keys_str_mv	AT kyliewhite antibacterialprofileofamicrobicidalagenttargetingtyrosinephosphatasesandredoxthiolsnoveldrugtargets AT ginanicoletti antibacterialprofileofamicrobicidalagenttargetingtyrosinephosphatasesandredoxthiolsnoveldrugtargets AT hughcornell antibacterialprofileofamicrobicidalagenttargetingtyrosinephosphatasesandredoxthiolsnoveldrugtargets
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Antibacterial Profile of a Microbicidal Agent Targeting Tyrosine Phosphatases and Redox Thiols, Novel Drug Targets

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