Discovery ofas a global regulator of secondary metabolism and virulence inE264.

TitleDiscovery ofas a global regulator of secondary metabolism and virulence inE264.
Publication TypeJournal Article
Year of Publication2017
AuthorsMao, D, Bushin, LB, Moon, K, Wu, Y, Seyedsayamdost, MR
JournalProc Natl Acad Sci U S A
Volume114
Issue14
PaginationE2920-E2928
Date Published2017 Apr 04
ISSN1091-6490
Abstract

Bacteria produce a diverse array of secondary metabolites that have been invaluable in the clinic and in research. These metabolites are synthesized by dedicated biosynthetic gene clusters (BGCs), which assemble architecturally complex molecules from simple building blocks. The majority of BGCs in a given bacterium are not expressed under normal laboratory growth conditions, and our understanding of how they are silenced is in its infancy. Here, we have addressed this question in the Gram-negative model bacteriumE264 using genetic, transcriptomic, metabolomic, and chemical approaches. We report that a previously unknown, quorum-sensing-controlled LysR-type transcriptional regulator, which we name ScmR (for secondary metabolite regulator), serves as a global gatekeeper of secondary metabolism and a repressor of numerous BGCs. Transcriptionally, we find that 13 of the 20 BGCs inare significantly (threefold or more) up- or down-regulated in adeletion mutant (Metabolically, thestrain displays a hyperactive phenotype relative to wild type and overproduces a number of compound families by 18- to 210-fold, including the silent virulence factor malleilactone. Accordingly, themutant is hypervirulent both in vitro and in amodel in vivo. Aside from secondary metabolism, ScmR also represses biofilm formation and transcriptionally activates ATP synthesis and stress response. Collectively, our data suggest that ScmR is a pleiotropic regulator of secondary metabolism, virulence, biofilm formation, and other stationary phase processes. A model for how the interplay of ScmR with pathway-specific transcriptional regulators coordinately silences virulence factor production is proposed.

DOI10.1073/pnas.1619529114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28320949
PubMed Central IDPMC5389298