Regulation of antibiotic production in Actinobacteria: new perspectives from the post-genomic era

Abstract

Covering: 2000 to 2018 The antimicrobial activity of many of their natural products has brought prominence to the Streptomycetaceae, a family of Gram-positive bacteria that inhabit both soil and aquatic sediments. In the natural environment, antimicrobial compounds are likely to limit the growth of competitors, thereby offering a selective advantage to the producer, in particular when nutrients become limited and the developmental programme leading to spores commences. The study of the control of this secondary metabolism continues to offer insights into its integration with a complex lifecycle that takes multiple cues from the environment and primary metabolism. Such information can then be harnessed to devise laboratory screening conditions to discover compounds with new or improved clinical value. Here we provide an update of the review we published in NPR in 2011. Besides providing the essential background, we focus on recent developments in our understanding of the underlying regulatory networks, ecological triggers of natural product biosynthesis, contributions from comparative genomics and approaches to awaken the biosynthesis of otherwise silent or cryptic natural products. In addition, we highlight recent discoveries on the control of antibiotic production in other Actinobacteria, which have gained considerable attention since the start of the genomics revolution. New technologies that have the potential to produce a step change in our understanding of the regulation of secondary metabolism are also described.

Antibiotic production is organized by a division of labour inStreptomyces

“…Vegetative hyphae secrete a broad variety of public goods, such as chitinases and cellulases that are used to acquire resources, as well as a chemically diverse suite of antibiotics that are used to kill or inhibit competing organisms 15–17 . Streptomycetes are prolific producers of antibiotics, and are responsible for producing more than 50% of our clinically relevant antibiotics 18 . Although the terminal differentiation of Streptomyces colonies into vegetative hyphae (soma) and viable spores (germ) is well understood 19–21 , no other divisions of labour in these multicellular bacteria are known.…”

Bagremycin Antibiotics and Ferroverdin iron-chelators are synthetized by the Same Gene Cluster

“…Genome sequencing of secondary metabolite-producing microorganisms has revealed the enormous potential to increase the known chemical space [5], with the promise of new leads in human therapies or for sustainable agriculture. One of the drivers of the renewed interest in natural products (NPs) was the discovery of so-called cryptic BGCs that are silent under routine laboratory conditions and may therefore specify molecules that had so far been missed during pharmaceutical screening [7][8][9]. An approach that is rapidly gaining momentum is to express cryptic BGCs in a heterologous chassis strain or superhost, and change promoter elements within the BGC by those that are expected to result in high expression under laboratory conditions.…”

Regulation of antimycin biosynthesis is controlled by the ClpXP protease

“…All data available indicates that the production of natural products is controlled predominantly at the level of transcription. Although there are complex regulatory cascades that tightly control expression of biosynthetic genes, they are ultimately activated, repressed or de-repressed by so-called cluster-situated regulators—regulatory protein(s) encoded within the biosynthetic gene cluster (BGC) 3,4 . Major roadblocks preventing the exploitation of silent biosynthetic pathways are a lack of insight into their regulation and limited technology for activating their expression.…”