Interplay between Nucleoid-Associated Proteins and Transcription Factors in Controlling Specialized Metabolism in Streptomyces

Abstract

Specialized metabolic clusters in Streptomyces are the source of many clinically prescribed antibiotics. However, many clusters are not expressed in the laboratory due to repression by the nucleoid-associated protein Lsr2.

Cryptic specialized metabolites drive Streptomyces exploration and provide a competitive advantage during growth with other microbes

“…In contrast, conditioned YPG agar plugs yielded robust inhibition zones. As one of the up-regulated gene clusters directs chloramphenicol synthesis (where chloramphenicol is a known antibiotic), we took advantage of a mutant that is deficient in chloramphenicol-production (Δ cmlR ; 22 ) and tested the antibiotic production potential of this strain when grown on YPG. Surprisingly, growth inhibition of M. luteus was comparable between the wild type and mutant strains, suggesting that another antibiotic must be contributing to the observed inhibition ( Fig.…”

AdpA Positively Regulates Morphological Differentiation and Chloramphenicol Biosynthesis in Streptomyces venezuelae

“…Here, we demonstrate for the first time that adpA of S. venezuelae might be essential for the production of chloramphenicol, since disruption of this gene abolishes the biosynthesis of this medically important antibiotic. Four other regulators responsible for controlling gene expression within Cm-BGC have been identified to date, including both global regulators (MtrA and Lsr2) and local regulators (JadR1 and CmlR, which are involved in the production of jadomycin and chloramphenicol, respectively) ( 65 – 69 ). Binding sites within the chloramphenicol gene cluster were previously identified for these regulators but not for AdpA.…”

“…S9 and Table S3). The former gene encodes CmlR, which is a key transcriptional regulator that is indispensable for chloramphenicol synthesis ( 53 , 69 ). Since some of these genes form operons (Fig.…”

“…The regulation of gene transcription in the Cm-BGC is still not clear. Recent discoveries indicate that the master regulator of secondary metabolism, Lsr2, may repress gene expression within Cm-BGC by looping distant regions of this gene cluster ( 69 ) and that CmlR, by binding within cmlI - cmlM intergenic region, can counteract Lsr2-mediated repression to allow transcription of biosynthetic genes. The putative binding sites of AdpA and CmlR overlap within the cmlI - cmlM region, suggesting that there may be an interplay between these two proteins.…”

“…The regulator, CmlR (also referred to as vnz_04400 or sven0913), is present in the chloramphenicol gene cluster and was found to play a crucial role in activating gene expression within this cluster. A very recently proposed mechanism explains the interplay between CmlR and the global transcriptional repressor, Lsr2, in regulating gene expression within the chloramphenicol biosynthetic gene cluster (Cm-BGC) ( 69 ). Despite these recent discoveries, however, we still know little about the roles of MtrA, JadR1, and AdpA in S. venezuelae .…”