Dataset Information

Production of ammonia as a low-cost and long-distance antibiotic strategy by Streptomyces species.

ABSTRACT: Soil-inhabiting streptomycetes are nature's medicine makers, producing over half of all known antibiotics and many other bioactive natural products. However, these bacteria also produce many volatiles, molecules that disperse through the soil matrix and may impact other (micro)organisms from a distance. Here, we show that soil- and surface-grown streptomycetes have the ability to kill bacteria over long distances via air-borne antibiosis. Our research shows that streptomycetes do so by producing surprisingly high amounts of the low-cost volatile ammonia, dispersing over long distances to inhibit the growth of Gram-positive and Gram-negative bacteria. Glycine is required as precursor to produce ammonia, and inactivation of the glycine cleavage system nullified ammonia biosynthesis and concomitantly air-borne antibiosis. Reduced expression of the porin master regulator OmpR and its cognate kinase EnvZ is used as a resistance strategy by E. coli cells to survive ammonia-mediated antibiosis. Finally, ammonia was shown to enhance the activity of canonical antibiotics, suggesting that streptomycetes adopt a low-cost strategy to sensitize competitors for antibiosis from a distance.

SUBMITTER: Avalos M

PROVIDER: S-EPMC6976574 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Production of ammonia as a low-cost and long-distance antibiotic strategy by Streptomyces species.

Avalos Mariana M Garbeva Paolina P Raaijmakers Jos M JM van Wezel Gilles P GP

The ISME journal 20191107 2

Soil-inhabiting streptomycetes are nature's medicine makers, producing over half of all known antibiotics and many other bioactive natural products. However, these bacteria also produce many volatiles, molecules that disperse through the soil matrix and may impact other (micro)organisms from a distance. Here, we show that soil- and surface-grown streptomycetes have the ability to kill bacteria over long distances via air-borne antibiosis. Our research shows that streptomycetes do so by producing ...[more]

PMID: 31700119

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Project description:One of the most important ways that bacteria compete for resources and space is by producing antibiotics that inhibit competitors. Because antibiotic production is costly, the biosynthetic gene clusters coordinating their synthesis are under strict regulatory control and often require "elicitors" to induce expression, including cues from competing strains. Although these cues are common, they are not produced by all competitors, and so the phenotypes causing induction remain unknown. By studying interactions between 24 antibiotic-producing strains of streptomycetes, we show that strains commonly inhibit each other's growth and that this occurs more frequently if strains are closely related. Next, we show that antibiotic production is more likely to be induced by cues from strains that are closely related or that share secondary metabolite biosynthetic gene clusters (BGCs). Unexpectedly, antibiotic production is less likely to be induced by competitors that inhibit the growth of a focal strain, indicating that cell damage is not a general cue for induction. In addition to induction, antibiotic production often decreases in the presence of a competitor, although this response was not associated with genetic relatedness or overlap in BGCs. Finally, we show that resource limitation increases the chance that antibiotic production declines during competition. Our results reveal the importance of social cues and resource availability in the dynamics of interference competition in streptomycetes.IMPORTANCE Bacteria secrete antibiotics to inhibit their competitors, but the presence of competitors can determine whether these toxins are produced. Here, we study the role of the competitive and resource environment on antibiotic production in Streptomyces, bacteria renowned for their production of antibiotics. We show that Streptomyces cells are more likely to produce antibiotics when grown with competitors that are closely related or that share biosynthetic pathways for secondary metabolites, but not when they are threatened by competitor's toxins, in contrast to predictions of the competition sensing hypothesis. Streptomyces cells also often reduce their output of antibiotics when grown with competitors, especially under nutrient limitation. Our findings highlight that interactions between the social and resource environments strongly regulate antibiotic production in these medicinally important bacteria.

Project description:Cyclic AMP receptor protein (Crp) is a transcription regulator controlling diverse cellular processes in many bacteria. In Streptomyces coelicolor, it is well established that Crp plays a critical role in spore germination and colony development. Here, we demonstrate that Crp is a key regulator of secondary metabolism and antibiotic production in S. coelicolor and show that it may additionally coordinate precursor flux from primary to secondary metabolism. We found that crp deletion adversely affected the synthesis of three well-characterized antibiotics in S. coelicolor: actinorhodin (Act), undecylprodigiosin (Red), and calcium-dependent antibiotic (CDA). Using chromatin immunoprecipitation-microarray (ChIP-chip) assays, we determined that eight (out of 22) secondary metabolic clusters encoded by S. coelicolor contained Crp-associated sites. We followed the effect of Crp induction using transcription profiling analyses and found secondary metabolic genes to be significantly affected: included in this Crp-dependent group were genes from six of the clusters identified in the ChIP-chip experiments. Overexpressing Crp in a panel of Streptomyces species led to enhanced antibiotic synthesis and new metabolite production, suggesting that Crp control over secondary metabolism is broadly conserved in the streptomycetes and that Crp overexpression could serve as a powerful tool for unlocking the chemical potential of these organisms. IMPORTANCE Streptomyces produces a remarkably diverse array of secondary metabolites, including many antibiotics. In recent years, genome sequencing has revealed that these products represent only a small proportion of the total secondary metabolite potential of Streptomyces. There is, therefore, considerable interest in discovering ways to stimulate the production of new metabolites. Here, we show that Crp (the classical regulator of carbon catabolite repression in Escherichia coli) is a master regulator of secondary metabolism in Streptomyces. It binds to eight of 22 secondary metabolic gene clusters in the Streptomyces coelicolor genome and directly affects the expression of six of these. Deletion of crp in S. coelicolor leads to dramatic reductions in antibiotic levels, while Crp overexpression enhances antibiotic production. We find that the antibiotic-stimulatory capacity of Crp extends to other streptomycetes, where its overexpression activates the production of "cryptic" metabolites that are not otherwise seen in the corresponding wild-type strain.

Dataset Information

Production of ammonia as a low-cost and long-distance antibiotic strategy by Streptomyces species.

Publications

Production of ammonia as a low-cost and long-distance antibiotic strategy by Streptomyces species.

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