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

Heul, Helga U. van der; Bilyk, Bohdan; McDowall, Kenneth J.; Seipke, Ryan F.; Wezel, Gilles P. van

doi:10.1039/c8np00012c

Cited by 196 publications

(162 citation statements)

References 400 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Antibiotic production is organized by a division of labour inStreptomyces

Zhang

Barsy

Liem

et al. 2019

Preprint

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26One of the hallmark behaviors of social groups is division of labour, where different group members 27 become specialized to carry out complementary tasks. By dividing labour, cooperative groups of 28 individuals increase their efficiency, thereby raising group fitness even if these specialized behaviors 29reduce the fitness of individual group members. Here we provide evidence that antibiotic production 30 in colonies of the multicellular bacterium Streptomyces coelicolor is coordinated by a division of labour. 31We show that S. coelicolor colonies are genetically heterogeneous due to massive amplifications and 32 deletions to the chromosome. Cells with gross chromosomal changes produce an increased diversity 33 of secondary metabolites and secrete significantly more antibiotics; however, these changes come at 34 the cost of dramatically reduced individual fitness, providing direct evidence for a trade-off between 35 secondary metabolite production and fitness. Finally, we show that colonies containing mixtures of 36 mutant strains and their parents produce significantly more antibiotics, while colony-wide spore 37 production remains unchanged. Our work demonstrates that by generating mutants that are 38 specialized to hyper-produce antibiotics, streptomycetes reduce the colony-wide fitness costs of 39 secreted secondary metabolites while maximizing the yield and diversity of these products. 40

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Section: Introductionmentioning

confidence: 99%

Antibiotic production is organized by a division of labour inStreptomyces

Zhang

Barsy

Liem

et al. 2019

Preprint

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Martinet

Naômé

Deflandre

et al. 2019

Preprint

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Biosynthetic gene clusters (BGCs) are organized groups of genes involved in the production of specialized metabolites. Typically, one BGC is responsible for the production of one or several similar compounds with bioactivities that usually only vary in terms of strength and/or specificity. Here we show that the previously described ferroverdins and bagremycins, which are families of metabolites with different bioactivities, are produced from the same BGC, whereby the fate of the biosynthetic pathway depends on iron availability. Under conditions of iron depletion, the monomeric bagremycins are formed, which are amino-aromatic antibiotics resulting from the condensation of 3-amino-4-hydroxybenzoic acid with p-vinylphenol.Conversely, when iron is abundantly available, the biosynthetic pathway additionally produces a molecule based on p-vinylphenyl-3-nitroso-4-hydroxybenzoate, which complexes iron to form the trimeric ferroverdins that have anticholesterol activity. Thus our work challenges the concept that BGCs should produce a single family of molecules with one type of bioactivity, the occurrence of the different metabolites being triggered by the environmental conditions.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Regulation of antimycin biosynthesis is controlled by the ClpXP protease

Bilyk

Fazal

Baker

et al. 2019

Preprint

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AbstractThe survival of any microbe relies upon its ability to respond to environmental change. Use of Extra Cytoplasmic Function (ECF) RNA polymerase sigma (σ) factors is a major strategy enabling dynamic responses to extracellular signals. Streptomyces species harbor a large number of ECF σ factors; nearly all of which regulate genes required for morphological differentiation and/or response to environmental stress, except for σAntA, which regulates starter-unit biosynthesis in the production of antimycin, an anticancer compound. Unlike a canonical ECF σ factor, whose activity is regulated by a cognate anti-σ factor, σAntA is an orphan, raising intriguing questions about how its activity may be controlled. Here, we reconstitute in vitro ClpXP proteolysis of σAntA, but not a variant lacking a C-terminal di-alanine motif. Furthermore, we show that the abundance of σAntAin vivo is enhanced by removal of the ClpXP recognition sequence, and that levels of the protein rise when cellular ClpXP protease activity is abolished. These data establish direct proteolysis as an alternative and thus far unique control strategy for an ECF RNA polymerase σ factor and expands the paradigmatic understanding of microbial signal transduction regulation.ImportanceNatural products produced by Streptomyces species underpin many industrially- and medically-important compounds. However, the majority of the ~30 biosynthetic pathways harboured by an average species are not expressed in the laboratory. This undiscovered biochemical diversity is believed to comprise an untapped resource for natural products drug discovery. A major roadblock preventing the exploitation of unexpressed biosynthetic pathways is a lack of insight into their regulation and limited technology for activating their expression. Our findings reveal that the abundance of σAntA, which is the cluster-situated regulator of antimycin biosynthesis, is controlled by the ClpXP protease. These data link proteolysis to the regulation of natural product biosynthesis for the first time and we anticipate that this will emerge as a major strategy by which actinobacteria regulate production of their natural products. Further study of this process will advance understanding of how expression of secondary metabolism is controlled and will aid pursuit of activating unexpressed biosynthetic pathways.

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

Cited by 196 publications

References 400 publications

Antibiotic production is organized by a division of labour inStreptomyces

Antibiotic production is organized by a division of labour inStreptomyces

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

Regulation of antimycin biosynthesis is controlled by the ClpXP protease

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