Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in .

TitlePiperacillin triggers virulence factor biosynthesis via the oxidative stress response in .
Publication TypeJournal Article
Year of Publication2021
AuthorsLi, A, Okada, BK, Rosen, PC, Seyedsayamdost, MR
JournalProc Natl Acad Sci U S A
Volume118
Issue26
Date Published2021 Jun 29
ISSN1091-6490
Abstract

<p>Natural products have been an important source of therapeutic agents and chemical tools. The recent realization that many natural product biosynthetic genes are silent or sparingly expressed during standard laboratory growth has prompted efforts to investigate their regulation and develop methods to induce their expression. Because it is difficult to intuit signals that induce a given biosynthetic locus, we recently implemented a forward chemical-genetic approach to identify such inducers. In the current work, we applied this approach to nine silent biosynthetic loci in the model bacterium to systematically screen for elicitors from a library of Food and Drug Administration-approved drugs. We find that β-lactams, fluoroquinolones, antifungals, and, surprisingly, calcimimetics, phenothiazine antipsychotics, and polyaromatic antidepressants are the most effective global inducers of biosynthetic genes. Investigations into the mechanism of stimulation of the silent virulence factor malleicyprol by the β-lactam piperacillin allowed us to elucidate the underlying regulatory circuits. Low-dose piperacillin causes oxidative stress, thereby inducing redox-sensing transcriptional regulators, which activate , a pathway-specific positive regulator of the malleicyprol gene cluster. Malleicyprol is thus part of the OxyR and SoxR regulons in , allowing the bacterium to initiate virulence in response to oxidative stress. Our work catalogs a diverse array of elicitors and a previously unknown regulatory input for secondary metabolism in .</p>

DOI10.1073/pnas.2021483118
Alternate JournalProc Natl Acad Sci U S A
PubMed ID34172579
PubMed Central IDPMC8256049
Grant ListDP2 AI124786 / AI / NIAID NIH HHS / United States