Mervyn Bibb

Mervyn Bibb
Biotechnology and Biological Sciences Research Council | BBSRC

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271
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Publications

Publications (271)
Article
Full-text available
Streptomyces clavuligerus is an industrially important actinomycete whose genetic manipulation is limited by low transformation and conjugation efficiencies, low levels of recombination of introduced DNA, and difficulty in obtaining consistent sporulation. We describe the construction and application of versatile vectors for Cas9-mediated genome ed...
Article
For over a decade, Streptomyces venezuelae has been used to study the molecular mechanisms that control morphological development in streptomycetes and it is now a well-established model strain. Its rapid growth and ability to sporulate in a near-synchronised manner in liquid culture, unusual among streptomycetes, greatly facilitates the applicatio...
Article
Full-text available
The discovery of novel antibiotics to tackle the growing threat of antimicrobial resistance is impeded by difficulties in accessing the full biosynthetic potential of microorganisms. The development of new tools to unlock the biosynthesis of cryptic bacterial natural products will greatly increase the repertoire of natural product scaffolds. Here,...
Article
Full-text available
Recent developments in genome sequencing combined with bioinformatic analysis have revealed that actinomycetes contain a plethora of unexpected BGCs and thus have the potential to produce many more natural products than previously thought. This reflects the inability to detect the production of these compounds under laboratory conditions, perhaps t...
Preprint
Full-text available
Most clinical antibiotics are derived from actinomycete natural products (NPs) discovered at least 60 years ago. Repeated rediscovery of known compounds led the pharmaceutical industry to largely discard microbial NPs as a source of new chemical diversity but advances in genome sequencing revealed that these organisms have the potential to make man...
Article
Full-text available
Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bacteri...
Data
Methods S1. PDF file containing methods for semi-synthetic synthesis of the TUN-X,X analogues and related compounds. Related to Figure 5
Article
Full-text available
Streptomyces leeuwenhoekii strains C34T, C38, C58 and C79 were isolated from a soil sample collected from the Chaxa Lagoon, located in the Salar de Atacama in northern Chile. These streptomycetes produce a variety of new specialised metabolites with antibiotic, anti-cancer and anti-inflammatory activities. Moreover, genome mining performed on two o...
Article
The tunicamycin biosynthetic gene cluster of Streptomyces chartreusis consists of 14 genes ( tunA-N ) with a high degree of apparent translational coupling. Transcriptional analysis revealed that all of these genes are likely to be transcribed as a single operon from two promoters, tun p1 and tun p2. In frame deletion analysis revealed that just si...
Preprint
Full-text available
Protein glycosylation is a widespread post-translational modification. The first committed step to the lipid-linked glycan used for this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and congenital disorders of glycosylation...
Article
Full-text available
Streptomyces leeuwenhoekii, isolated from the hyper arid Atacama Desert, produces the new ansamycin-like compounds chaxamycin A-D, which possess potent antibacterial activity and moderate antiproliferative activity. We report the development of genetic tools to manipulate S. leeuwenhoekii, and the identification and partial characterisation of the...
Article
Full-text available
Next Generation DNA Sequencing (NGS) and genome mining of actinomycetes and other microorganisms is currently one of the most promising strategies for the discovery of novel bioactive natural products, potentially revealing novel chemistry and enzymology involved in their biosynthesis. This approach also allows rapid insights into the biosynthetic...
Article
Full-text available
The search for new natural products is leading to the isolation of novel actinomycete species, many of which will ultimately require genetic analysis. Some of these isolates will likely exhibit low intrinsic frequencies of homologous recombination and fail to sporulate under laboratory conditions, exacerbating the construction of targeted gene dele...
Article
Full-text available
Comparative genome analysis revealed seven uncharacterized genes, sven0909 to sven0915, adjacent to the previously identified chloramphenicol biosynthetic gene cluster (sven0916–sven0928) of Streptomyces venezuelae strain ATCC 10712 that was absent in a closely related Streptomyces strain that does not produce chloramphenicol. Transcriptional analy...
Article
Full-text available
Glycopeptides and β-lactams inhibit bacterial peptidoglycan synthesis in Gram-positive bacteria; resistance to these antibiotics is studied intensively in enterococci and staphylococci because of their relevance to infectious disease. Much less is known about antibiotic resistance in glycopeptide-producing actinomycetes that are likely to represent...
Article
Actinomycetes are prolific producers of natural products with a wide range of biological activities. Many of the compounds that they make (and derivatives thereof) are used extensively in medicine, most notably as clinically important antibiotics, and in agriculture. Moreover, these organisms remain a source of novel and potentially useful molecule...
Article
Heterologous gene expression is one of the main strategies used to access the full biosynthetic potential of actinomycetes, as well as to study the metabolic pathways of natural product biosynthesis and to create unnatural pathways. Streptomyces coelicolor A3(2) is the most studied member of the actinomycetes, bacteria renowned for their prolific c...
Article
Full-text available
We describe a procedure for the conjugative transfer of phage P1-derived Artificial Chromosome (PAC) library clones containing large natural product gene clusters (≥70 kilobases) to Streptomyces coelicolor strains that have been engineered for improved heterologous production of natural products. This approach is demonstrated using the gene cluster...
Data
LCMS-MS analysis of FK506 standard (top) and FK506 produced by Streptomyces coelicolor M1146/PAC20N#3 (bottom). The parent ion is the sodium adduct of FK506 (826.7 m/z). (TIF)
Article
Full-text available
We demonstrate the first application of synthetic RNA gene silencers in Streptomyces coelicolor A3(2). Peptide nucleic acid and expressed antisense RNA silencers successfully inhibited actinorhodin production. Synthetic RNA silencing was target-specific and is a new tool for gene regulation and metabolic engineering studies in Streptomyces.
Data
Schematic representation of the cloning strategy used to construct antisense RNA expressing vector pAS02. (TIFF)
Data
Calcium-dependent antibiotic assay. The assay was performed as previously reported [34] using B. mycoides as the indicator strain (A) wild-type S. coelicolor MT1110. (B) MT1110/pAS01 induced by adding thiostrepton to the agar. Plates were photographed and half images from each strain were aligned to compare the size of the zone of inhibition. (PNG)
Data
Off-target matches in S. coelicolor for PNAs used in this study. (DOCX)
Article
Planosporicin is a ribosomally synthesized, posttranslationally modified peptide lantibiotic produced by the actinomycete Planomonospora alba. It contains one methyl-lanthionine and four lanthionine bridges and inhibits cell wall biosynthesis in other Gram-positive bacteria probably by binding to lipid II, the immediate precursor for cell wall bios...
Article
Full-text available
Consistent with their complex lifestyles and rich secondary metabolite profiles, the genomes of streptomycetes encode a plethora of transcription factors, the vast majority of which are uncharacterized. Herein, we use Surface Plasmon Resonance (SPR) to identify and delineate putative operator sites for SCO3205, a MarR family transcriptional regulat...
Article
Full-text available
The increasing prevalence of antibiotic resistance in bacterial pathogens has renewed focus on natural products with antimicrobial properties. Lantibiotics are ribosomally-synthesized peptide antibiotics that are post-translationally modified to introduce (methyl)lanthionine bridges. Actinomycetes are renowned for their ability to produce a large v...
Article
The crystal structure of Sco5413 from Streptomyces coelicolor A3(2) has been determined at 1.25 Å resolution, the highest resolution reported for a MarR family transcriptional regulator. Putative orthologs are encoded by the majority of sequenced actinomycete genomes, and may play roles in regulating growth and antibiotic production, but they have...
Article
Full-text available
Covering: 1988 to 2012This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.
Article
Bottromycins are unique peptide antibiotics that contain a macrolactamidine, several non-proteinogenic amino acids and a thiazole. We hypothesised that the bottromycins originate from a ribosomally biosynthesised precursor that is elaborated to the mature antibiotics via a series of unusual posttranslational modifications, including β-methylation o...
Article
The expression of a gene or a set of genes from one organism in a different species is known as "heterologous expression." In actinomycetes, prolific producers of natural products, heterologous gene expression has been used to confirm the clustering of secondary metabolite biosynthetic genes, to analyze natural product biosynthesis, to produce vari...
Article
Cryptic natural product biosynthetic pathways discovered by genome mining are a promising source of novel bioactive natural products. Here we report the identification, isolation and structure elucidation of coelimycin P1, an unusual yellow-pigmented metabolic product of the cpk cryptic polyketide biosynthetic gene cluster of Streptomyces coelicolo...
Article
Bioinformatics analyses have identified gene clusters encoding cryptic polyketide biosynthetic pathways, not associated with the production of known metabolites, in several actinomycete genome sequences. Discovery of the metabolic products of such cryptic gene clusters promises to unearth a hitherto untapped wealth of novel bioactive compounds. How...
Article
Full-text available
The tunicamycins are archetypal nucleoside antibiotics targeting bacterial peptidoglycan biosynthesis and eukaryotic protein N-glycosylation. Understanding the biosynthesis of their unusual carbon framework may lead to variants with improved selectivity. Here, we demonstrate in vitro recapitulation of key sugar-manipulating enzymes from this pathwa...
Article
Gene clusters found in bacterial species classified as Streptomyces encode the majority of known antibiotics as well as many pharmaceutically active compounds. A site-specific recombination system similar to those that mediate plasmid conjugation was engineered to catalyze tandem amplification of one of these gene clusters in a heterologous Strepto...
Article
Full-text available
Verrucosispora maris AB-18-032 is a marine actinomycete that produces atrop-abyssomicin C and proximicin A, both of which have novel structures and modes of action. In order to understand the biosynthesis of these compounds, to identify further biosynthetic potential, and to facilitate rational improvement of secondary metabolite titers, we have se...
Article
Full-text available
Streptomyces spp. are common symbionts of the leaf-cutting ant species Acromyrmex octospinosus, which feeds on basidiomycete fungus leaf matter and harvests the lipid- and carbohydrate-rich gongylidia as a food source. A. octospinosus and other ant genera use antifungal compounds produced by Streptomyces spp. and other actinomycetes in order to hel...
Article
Full-text available
Small wonder: Atrop-abyssomicin C is a small, yet complex spirotetronate (see scheme) that is active against Gram-positive bacteria, such as MRSA. Feeding studies and genetic manipulation of its producer, Verrucosispora maris AB-18-032, for the first time give insight into its biosynthesis and demonstrate how closely related the members of this imp...
Article
Lantibiotics are ribosomally synthesized, posttranslationally modified peptide antibiotics. Microbisporicin is a potent lantibiotic produced by the actinomycete Microbispora corallina and contains unique chlorinated tryptophan and dihydroxyproline residues. The biosynthetic gene cluster for microbisporicin encodes several putative regulatory protei...
Data
Summary of transcriptome analysis of genes significantly differently expressed in response to vancomycin treatment.
Data
Summary of transcriptome analysis of genes significantly differently expressed in response to bacitracin treatment.
Data
Normalised expression data for the differentially expressed gene groups illustrated in the venn diagram of Figure 1B.
Data
MGSA GO analysis of the genes significantly differently expressed in response to vancomycin.
Data
MGSA GO analysis of the genes significantly differently expressed in response to bacitracin.
Data
Term for term GO analysis of the genes significantly differently expressed in response to vancomycin.
Data
Term for term GO analysis of the differentially expressed gene groups illustrated in the venn diagram of Figure 1B.
Data
Genes whose expression following treatment with all three antibiotics is closely correlated (Pearson correlation > 0. 9) with transcription of the cell wall stress sigma factor σE (SCO3356).
Data
Summary of transcriptome analysis of genes significantly differently expressed in response to moenomycin treatment.
Data
Term for term GO analysis of the genes significantly differently expressed in response to bacitracin.
Data
MGSA GO analysis of the genes significantly differently expressed in response to moenomycin.
Data
Full-text available
Heatmaps summarising the expression of genes significantly differently expressed in response to drug treatment, grouped according to related function.
Data
Term for term GO analysis of the genes significantly differently expressed in response to moenomycin.
Data
Analysis of the differentially expressed gene groups illustrated in the venn diagram of Figure 1B, looking for significant similarity with in-house curated lists of functionally related genes.
Article
Full-text available
A decline in the discovery of new antibacterial drugs, coupled with a persistent rise in the occurrence of drug-resistant bacteria, has highlighted antibiotics as a diminishing resource. The future development of new drugs with novel antibacterial activities requires a detailed understanding of adaptive responses to existing compounds. This study u...
Data
Full-text available
Microarray expression profiles of amtB-glnK-glnD, glnA and glnII over the wild-type, glnR and glnRII mutant time courses. Expression is the average of three biological replicates and normalised intensity is plotted on a log2 scale. Diagram adapted from GeneSpring 9.0 (Agilent).
Data
Full-text available
Full list of genes induced >2 upon nitrogen starvation, that are also repressed by ammonium.