Piperacillin triggers virulence factor biosynthesis via the oxidative stress response in Burkholderia thailandensis

Abstract

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 Burkholderia thailandensis 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 malR, a pathway-specific positive regulator of the malleicyprol gene cluster. Malleicyprol is thus part of the OxyR and SoxR regulons in B. thailandensis, 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 B. thailandensis.

Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

“…The half‐maximal elicitor concentration (EC 50 ) was in a similar concentration range, 16.9 μM, connecting cytotoxicity with elicitation. This observation is consistent with the notion of toxins serving as effective elicitors of secondary metabolism at low doses [34] . In follow‐up studies, we used 30 μM of 1 , close to its IC 50 concentration, to induce synthesis of cryptic metabolites.…”

Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus

“…This observation is consistent with the notion of toxins serving as effective elicitors of secondary metabolism at low doses. [34] In followup studies, we used 30 μM of 1, close to its IC 50 concentration, to induce synthesis of cryptic metabolites.…”

Quorum-sensing gene regulates hormetic effects induced by sulfonamides in Comamonadaceae

“…Some specific hormetic dose responses have been mechanistically explained, usually based on receptors and signaling pathways 16,18 . For example, low doses of piperacillin can trigger secondary metabolite biogenesis via the OxyR and SoxR regulons in Burkholderia thailandensis 19 ; neomycin and erythromycin can enhance bacterial bioluminescence in Vibrio fischeri via the LuxR quorum sensing (QS) system 20,21 ; and tetracycline can up-regulate type III secretion system expression and consequently biofilm formation in Pseudomonas aeruginosa 22 . Notably, although cell growth is one of the most common endpoints of hormesis, existing hormetic studies have mainly focused on microbial growth kinetics at hormetic concentrations of antibiotics [23][24][25][26][27][28][29] .…”