Antibiotic production is organized by a division of labour in<i>Streptomyces</i>

Zhang, Zheren; Barsy, Frederique de; Liem, Michael; Liakopoulos, Apostolos; Choi, Young Hae; Claessen, Dennis; Rozen, Daniel E.

doi:10.1101/560136

Cited by 3 publications

(10 citation statements)

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“…Actinobacterial genomes readily undergo rearrangements, whereby more than 1 Mb of genomic DNA can be lost [18, 21, 29]. Here, we provide evidence that protoplast formation and regeneration in K. viridifaciens can lead to profound genomic rearrangements in the chromosome as well as loss of (large parts of) the megaplasmid KVP1.…”

Section: Discussionmentioning

confidence: 79%

“…By sequencing one revertant that had lost KVP1 we found that this strain had also lost approximately 1.5 Mb of the right arm of the chromosome. Such genetic instability is typical of streptomycetes, and can affect morphological differentiation, but also phenotypic traits associated with natural products, such as pigmentation, antibiotic biosynthesis and antibiotic resistance [20, 21]. Transposable elements were suggested as the principal cause of genetic instability [33].…”

Section: Discussionmentioning

confidence: 99%

“…The frequency of aberrant phenotypes after protoplast regeneration is higher than the phenotypic heterogeneity obtained after outgrowth of spores, which typically is in the order of 1% [18, 21, 29, 33, 36, 37]. An explanation for the high frequency of aberrant mutants in colonies arising after protoplasting may relate to the activation of transposable elements contained in the terminal regions of the chromosome and/or the KVP1 plasmid.…”

Section: Discussionmentioning

confidence: 99%

“…Mycelial pellets were harvested by centrifugation at 4000 rpm for 15min. The preparation of plugs for PFGE was performed as previously described [21]. Plugs were made with SeaKem Gold agarose (Lonza, Switzerland), and the genomic DNA in the plugs was cut with AseI.…”

Section: Methodsmentioning

confidence: 99%

“…This wide range of genomic rearrangements is believed to be caused by transposition or homologous recombination, occurring actively within the chromosome or between the chromosome and linear plasmids [19]. Not surprisingly, these changes have profound effects on differentiation and specialized metabolite production [20, 21].…”

Section: Introductionmentioning

confidence: 99%

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Genome rearrangements and megaplasmid loss in the filamentous bacteriumKitasatospora viridifaciensare associated with protoplast formation and regeneration

Ramijan

Zhang

Wezel

et al. 2019

Preprint

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20Filamentous Actinobacteria are multicellular bacteria with linear replicons. Kitasatospora 21 viridifaciens DSM 40239 contains a linear 7.8 Mb chromosome and an autonomously 22 replicating plasmid KVP1 of 1.7 Mb. Here we show that lysozyme-induced protoplast 23 formation of the multinucleated mycelium of K. viridifaciens drives morphological diversity. 24Characterization and sequencing of an individual revertant colony that had lost the ability to 25 differentiate revealed that the strain had not only lost most of KVP1 but also carried lesions 26 in the right arm of the chromosome. Strikingly, the lesion sites were preceded by insertion 27 sequence elements, suggesting that the rearrangements may have been caused by 28 replicative transposition and homologous recombination between both replicons. These 29 data indicate that protoplast formation is a stressful process that can lead to profound 30 genetic changes. 31 34 metabolites are mostly used as weapons that provide protection against other 35 microorganisms and phages in the environment [1][2][3]. This is particularly useful for 36 filamentous organisms, given that they generally lack the ability to make flagella for escaping 37 dangerous situations. In addition, these bacteria are able to generate resistant spores that 38 can invade new environments after their dispersal. Germination of spores leads to the 39 formation of 1-2 germ tubes, which grow by tip extension, thereby establishing filamentous 40 cells called hyphae. Branching of hyphae leads to the formation of a multinucleated 41 vegetative mycelium, which forages and acquires nutrients by decomposing polymeric 42 substances. Stressful conditions (such as nutrient depletion) induce program cell death 43 (PCD) of the mycelium, which in turn triggers morphological and chemical differentiation [4].44 This developmental transition leads to the formation of specialized hyphae that grow into the 45 air, and the onset of production of a suite of bioactive compounds [5]. Eventually, the aerial 46 hyphae metamorphose into chains of grey-pigmented spores. Mutants that are unable to 47 establish an aerial mycelium are called bald (bld), while those that are not capable to form 48 spores are called white (whi) after their whitish color [6, 7]. 49Genome mining has been instrumental for the revival of drug discovery [8, 9]. Many 50 of the biosynthetic gene clusters that specify bioactive natural products are contained on 51 giant linear plasmids [10-13]. Although linear replicons are rare in many bacterial taxa, they 52 are common in Actinobacteria [14, 15]. In fact, Streptomyces chromosomes (between 8 and 53 10 Mb in size) are also linear and typically comprise a "core region" containing the essential 54 genes, and two variable "arms" with lengths ranging from 1.5 Mb to 2.3 Mb [16]. Like linear 55 plasmids, the linear chromosomes are capped by terminal proteins bound to the 5' end of 56 the DNA [17]. The chromosomal ends are genetically unstable, and readily undergo large 57 (up to 2 Mb) DNA rearrangements. Such...

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genome rearrangements and megaplasmid loss in the filamentous bacteriumKitasatospora viridifaciensare associated with protoplast formation and regeneration

Ramijan

Zhang

Wezel

et al. 2019

Preprint

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Comparative Genomic and Metabolic Analysis of Streptomyces sp. RB110 Morphotypes Illuminates Genomic Rearrangements and Formation of a New 46-Membered Antimicrobial Macrolide

Guo

Thiengmag

et al. 2021

ACS Chem. Biol.

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Morphotype switches frequently occur in Actinobacteria and are often associated with disparate natural product production. Here, we report on differences in the secondary metabolomes of two morphotypes of a Streptomyces species, including the discovery of a novel antimicrobial glycosylated macrolide, which we named termidomycin A. While exhibiting an unusual 46-member polyene backbone, termidomycin A (1) shares structural features with the clinically important antifungal agents amphotericin B and nystatin A1. Genomic analyses revealed a biosynthetic gene cluster encoding for a putative giant type I polyketide synthase (PKS), whose domain structure allowed us to propose the relative configuration of the 46-member macrolide. The architecture of the biosynthetic gene cluster was different in both morphotypes, thus leading to diversification of the product spectrum. Given the high frequency of genomic rearrangements in Streptomycetes, the metabolic analysis of distinct morphotypes as exemplified in this study is a promising approach for the discovery of bioactive natural products and pathways of diversification.

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Microbial Evolution on a Virtual Grain of Sand

Dijk¹

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Rather late to the game, I was 20 years old when I first read a proper textbook on the topic of biology. Where my rather basic biological education in secondary school was little more than a four-year-long anatomy lesson, this book discussed broad questions ranging from the stability of entire ecosystems, down to the finer details of microbial life. When I started studying biology a year later, it was understanding the latter microscale that inspired me most. However, it quickly became clear to me that the entire concept of "understanding something" required a lot of unpacking. One course, in particular, made it crystal clear to me that just knowing and naming all the components of a system is not enough. Instead, biological systems have a lot of moving parts and self-organised structures across different scales, all of which have been selected through Darwinian evolution through natural selection. Clearly, to grasp what is happening at the microscale, the process of evolution cannot simply be tossed aside as something that has happened in the past. Instead, how microbes have evolved, and how microbes are still evolving in the soils and lakes around us, is key to understanding them.In this thesis titled 'Microbial Evolution on a Virtual Grain of Sand', I report on the research we have done that shines light on life at the microscale. With a variety of models, we tackle questions like: How can microbial diversity emerge, and how is it maintained in the long term? How is diversity impacted by Horizontal Gene Transfer? How predictable is evolution? How can microbes avoid accumulating deleterious mutations? We address these questions, and more, all by designing computational models in which bacterial ecosystems live in silico, on a Virtual Grain of Sand. 1. Introduction 1 18 1.2. Life at the microscale 1.2 Life at the microscale 20 1.2. Life at the microscale 1. Introduction 1. Introduction 24 1.3. The flexible gene content of microorganisms Figure 1.6: When sampling multiple microbial genomes from the same strain or species, the total collection of genes ranges from "open" to "closed" pangenomes.these general patterns, the exact processes shaping pangenomes are not entirely established. It is however becoming increasingly clear that HGT, i.e. the ability of microbes to take up genes from their neighbours or from the environment, plays a crucial role.

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Antibiotic production is organized by a division of labour inStreptomyces

Cited by 3 publications

References 54 publications

Genome rearrangements and megaplasmid loss in the filamentous bacteriumKitasatospora viridifaciensare associated with protoplast formation and regeneration

Genome rearrangements and megaplasmid loss in the filamentous bacteriumKitasatospora viridifaciensare associated with protoplast formation and regeneration

Comparative Genomic and Metabolic Analysis of Streptomyces sp. RB110 Morphotypes Illuminates Genomic Rearrangements and Formation of a New 46-Membered Antimicrobial Macrolide

Microbial Evolution on a Virtual Grain of Sand

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