luxR Homolog-Linked Biosynthetic Gene Clusters in Proteobacteria

Abstract

Microbes are a major source of antibiotics, pharmaceuticals, and other bioactive compounds. The production of many specialized microbial metabolites is encoded in biosynthetic gene clusters (BGCs). A challenge associated with natural product discovery is that many BGCs are not expressed under laboratory growth conditions. Here we report a genome-mining approach to discover BGCs with luxR-type quorum sensing (QS) genes, which code for regulatory proteins that control gene expression. Our results show that BGCs linked to genes coding for LuxR-like proteins are widespread in Proteobacteria. In addition, we show that associations between luxR homolog genes and BGCs have evolved independently many times, with functionally diverse gene clusters. Overall, these clusters may provide a source of new natural products for which there is some understanding about how to elicit production. IMPORTANCE Bacteria biosynthesize specialized metabolites with a variety of ecological functions, including defense against other microbes. Genes that code for specialized metabolite biosynthetic enzymes are frequently clustered together. These BGCs are often regulated by a transcription factor encoded within the cluster itself. These pathway-specific regulators respond to a signal or indirectly through other means of environmental sensing. Many specialized metabolites are not produced under laboratory growth conditions, and one reason for this issue is that laboratory growth media lack environmental cues necessary for BGC expression. Here, we report a bioinformatics study that reveals that BGCs are frequently linked to genes coding for LuxR family QS-responsive transcription factors in the phylum Proteobacteria. The products of these luxR homolog-associated gene clusters may serve as a practical source of bioactive metabolites.

Keywords: quorum sensing; secondary metabolism.

FIG 1

Characterized LuxR-associated and QS-regulated BGCs were identified in our screen. The luxR and luxI homologs are shown in green and red, respectively, and all other genes in each biosynthetic cluster are shown in gray. The name of the BGC, the name of the producing organism, the type of BGC, and the structure of the encoded product are shown for each example. All three of these products have potent antimicrobial activity.

FIG 2

Pie charts showing the types of BGCs associated with luxR homologs (A) and the habitats of the organisms with luxR homolog-associated BGCs (B).