Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide

ABSTRACT Salmonella enterica serovar Typhimurium is an intracellular pathogen that elicits nitric oxide (NO·) production by host macrophages. NO· is a potent antimicrobial mediator with diverse targets, including protein thiols and metal centers. The mobilization of zinc from metalloproteins by NO·...

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Autores principales:	Anshika Singhal, Ferric C. Fang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	mismetallation peptide deformylase salmonella nitric oxide zinc homeostasis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/30091c9385584c8d849123329ef60762
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spelling	oai:doaj.org-article:30091c9385584c8d849123329ef607622021-11-15T15:55:43ZDirect and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide10.1128/mBio.01383-202150-7511https://doaj.org/article/30091c9385584c8d849123329ef607622020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01383-20https://doaj.org/toc/2150-7511ABSTRACT Salmonella enterica serovar Typhimurium is an intracellular pathogen that elicits nitric oxide (NO·) production by host macrophages. NO· is a potent antimicrobial mediator with diverse targets, including protein thiols and metal centers. The mobilization of zinc from metalloproteins by NO· increases the availability of free intracellular zinc, which is detrimental to bacterial cells, but the precise mechanism of zinc cytotoxicity is uncertain. Here, we show that excess zinc results in the mismetallation of the essential iron-containing enzyme peptide deformylase (PDF), thereby diminishing its activity. PDF mismetallation is observed in zinc-treated bacteria lacking the zinc exporters ZntA and ZitB and is also observed during nitrosative stress, suggesting that NO·-mediated zinc mobilization results in PDF mismetallation. However, NO· also inhibits PDF directly by S-nitrosylating the metal-binding Cys90 residue. These observations identify PDF as an essential bacterial protein that is subject to both direct and indirect inactivation by NO·, providing a novel mechanism of zinc toxicity and NO·-mediated antibacterial activity. IMPORTANCE We have previously shown that the host-derived antimicrobial mediator nitric oxide (NO·) mobilizes zinc from bacterial metalloproteins. The present study demonstrates that NO· inactivates the essential iron-containing enzyme peptide deformylase, both by promoting its mismetallation by zinc and by directly modifying its metal-binding site. We explain how free intracellular zinc is detrimental for cells and reveal a new mechanism of NO·-mediated bacterial growth inhibition that is distinct from previously known targets.Anshika SinghalFerric C. FangAmerican Society for Microbiologyarticlemismetallationpeptide deformylasesalmonellanitric oxidezinc homeostasisMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	mismetallation peptide deformylase salmonella nitric oxide zinc homeostasis Microbiology QR1-502
spellingShingle	mismetallation peptide deformylase salmonella nitric oxide zinc homeostasis Microbiology QR1-502 Anshika Singhal Ferric C. Fang Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
description	ABSTRACT Salmonella enterica serovar Typhimurium is an intracellular pathogen that elicits nitric oxide (NO·) production by host macrophages. NO· is a potent antimicrobial mediator with diverse targets, including protein thiols and metal centers. The mobilization of zinc from metalloproteins by NO· increases the availability of free intracellular zinc, which is detrimental to bacterial cells, but the precise mechanism of zinc cytotoxicity is uncertain. Here, we show that excess zinc results in the mismetallation of the essential iron-containing enzyme peptide deformylase (PDF), thereby diminishing its activity. PDF mismetallation is observed in zinc-treated bacteria lacking the zinc exporters ZntA and ZitB and is also observed during nitrosative stress, suggesting that NO·-mediated zinc mobilization results in PDF mismetallation. However, NO· also inhibits PDF directly by S-nitrosylating the metal-binding Cys90 residue. These observations identify PDF as an essential bacterial protein that is subject to both direct and indirect inactivation by NO·, providing a novel mechanism of zinc toxicity and NO·-mediated antibacterial activity. IMPORTANCE We have previously shown that the host-derived antimicrobial mediator nitric oxide (NO·) mobilizes zinc from bacterial metalloproteins. The present study demonstrates that NO· inactivates the essential iron-containing enzyme peptide deformylase, both by promoting its mismetallation by zinc and by directly modifying its metal-binding site. We explain how free intracellular zinc is detrimental for cells and reveal a new mechanism of NO·-mediated bacterial growth inhibition that is distinct from previously known targets.
format	article
author	Anshika Singhal Ferric C. Fang
author_facet	Anshika Singhal Ferric C. Fang
author_sort	Anshika Singhal
title	Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
title_short	Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
title_full	Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
title_fullStr	Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
title_full_unstemmed	Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide
title_sort	direct and indirect inhibition of <italic toggle="yes">salmonella</italic> peptide deformylase by nitric oxide
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/30091c9385584c8d849123329ef60762
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Direct and Indirect Inhibition of <italic toggle="yes">Salmonella</italic> Peptide Deformylase by Nitric Oxide

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