Protein interactions in genome maintenance as novel antibacterial targets.

Antibacterial compounds typically act by directly inhibiting essential bacterial enzyme activities. Although this general mechanism of action has fueled traditional antibiotic discovery efforts for decades, new antibiotic development has not kept pace with the emergence of drug resistant bacterial s...

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Autores principales:	Aimee H Marceau, Douglas A Bernstein, Brian W Walsh, Walker Shapiro, Lyle A Simmons, James L Keck
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3149b5ee7bc840abbfa3aae4813f54d4
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spelling	oai:doaj.org-article:3149b5ee7bc840abbfa3aae4813f54d42021-11-18T07:53:56ZProtein interactions in genome maintenance as novel antibacterial targets.1932-620310.1371/journal.pone.0058765https://doaj.org/article/3149b5ee7bc840abbfa3aae4813f54d42013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23536821/?tool=EBIhttps://doaj.org/toc/1932-6203Antibacterial compounds typically act by directly inhibiting essential bacterial enzyme activities. Although this general mechanism of action has fueled traditional antibiotic discovery efforts for decades, new antibiotic development has not kept pace with the emergence of drug resistant bacterial strains. These limitations have severely restricted the therapeutic tools available for treating bacterial infections. Here we test an alternative antibacterial lead-compound identification strategy in which essential protein-protein interactions are targeted rather than enzymatic activities. Bacterial single-stranded DNA-binding proteins (SSBs) form conserved protein interaction "hubs" that are essential for recruiting many DNA replication, recombination, and repair proteins to SSB/DNA nucleoprotein substrates. Three small molecules that block SSB/protein interactions are shown to have antibacterial activity against diverse bacterial species. Consistent with a model in which the compounds target multiple SSB/protein interactions, treatment of Bacillus subtilis cultures with the compounds leads to rapid inhibition of DNA replication and recombination, and ultimately to cell death. The compounds also have unanticipated effects on protein synthesis that could be due to a previously unknown role for SSB/protein interactions in translation or to off-target effects. Our results highlight the potential of targeting protein-protein interactions, particularly those that mediate genome maintenance, as a powerful approach for identifying new antibacterial compounds.Aimee H MarceauDouglas A BernsteinBrian W WalshWalker ShapiroLyle A SimmonsJames L KeckPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58765 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aimee H Marceau Douglas A Bernstein Brian W Walsh Walker Shapiro Lyle A Simmons James L Keck Protein interactions in genome maintenance as novel antibacterial targets.
description	Antibacterial compounds typically act by directly inhibiting essential bacterial enzyme activities. Although this general mechanism of action has fueled traditional antibiotic discovery efforts for decades, new antibiotic development has not kept pace with the emergence of drug resistant bacterial strains. These limitations have severely restricted the therapeutic tools available for treating bacterial infections. Here we test an alternative antibacterial lead-compound identification strategy in which essential protein-protein interactions are targeted rather than enzymatic activities. Bacterial single-stranded DNA-binding proteins (SSBs) form conserved protein interaction "hubs" that are essential for recruiting many DNA replication, recombination, and repair proteins to SSB/DNA nucleoprotein substrates. Three small molecules that block SSB/protein interactions are shown to have antibacterial activity against diverse bacterial species. Consistent with a model in which the compounds target multiple SSB/protein interactions, treatment of Bacillus subtilis cultures with the compounds leads to rapid inhibition of DNA replication and recombination, and ultimately to cell death. The compounds also have unanticipated effects on protein synthesis that could be due to a previously unknown role for SSB/protein interactions in translation or to off-target effects. Our results highlight the potential of targeting protein-protein interactions, particularly those that mediate genome maintenance, as a powerful approach for identifying new antibacterial compounds.
format	article
author	Aimee H Marceau Douglas A Bernstein Brian W Walsh Walker Shapiro Lyle A Simmons James L Keck
author_facet	Aimee H Marceau Douglas A Bernstein Brian W Walsh Walker Shapiro Lyle A Simmons James L Keck
author_sort	Aimee H Marceau
title	Protein interactions in genome maintenance as novel antibacterial targets.
title_short	Protein interactions in genome maintenance as novel antibacterial targets.
title_full	Protein interactions in genome maintenance as novel antibacterial targets.
title_fullStr	Protein interactions in genome maintenance as novel antibacterial targets.
title_full_unstemmed	Protein interactions in genome maintenance as novel antibacterial targets.
title_sort	protein interactions in genome maintenance as novel antibacterial targets.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/3149b5ee7bc840abbfa3aae4813f54d4
work_keys_str_mv	AT aimeehmarceau proteininteractionsingenomemaintenanceasnovelantibacterialtargets AT douglasabernstein proteininteractionsingenomemaintenanceasnovelantibacterialtargets AT brianwwalsh proteininteractionsingenomemaintenanceasnovelantibacterialtargets AT walkershapiro proteininteractionsingenomemaintenanceasnovelantibacterialtargets AT lyleasimmons proteininteractionsingenomemaintenanceasnovelantibacterialtargets AT jameslkeck proteininteractionsingenomemaintenanceasnovelantibacterialtargets
_version_	1718422776083120128

Protein interactions in genome maintenance as novel antibacterial targets.

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