Future directions for the discovery of antibiotics from actinomycete bacteria

2017 ◽  
Vol 1 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Rebecca Devine ◽  
Matthew I. Hutchings ◽  
Neil A. Holmes
Keyword(s):  
New Technologies ◽  
Gene Clusters ◽  
Biosynthetic Gene Clusters ◽  
Future Directions ◽  
Streptomyces Species ◽  
Genus Streptomyces ◽  
New Antibiotics ◽  
The Uk ◽  
Almost All ◽  
New Generation

Antimicrobial resistance (AMR) is a growing societal problem, and without new anti-infective drugs, the UK government-commissioned O'Neil report has predicted that infectious disease will claim the lives of an additional 10 million people a year worldwide by 2050. Almost all the antibiotics currently in clinical use are derived from the secondary metabolites of a group of filamentous soil bacteria called actinomycetes, most notably in the genus Streptomyces. Unfortunately, the discovery of these strains and their natural products (NPs) peaked in the 1950s and was then largely abandoned, partly due to the repeated rediscovery of known strains and compounds. Attention turned instead to rational target-based drug design, but this was largely unsuccessful and few new antibiotics have made it to clinic in the last 60 years. In the early 2000s, however, genome sequencing of the first Streptomyces species reinvigorated interest in NP discovery because it revealed the presence of numerous cryptic NP biosynthetic gene clusters that are not expressed in the laboratory. Here, we describe how the use of new technologies, including improved culture-dependent and -independent techniques, combined with searching underexplored environments, promises to identify a new generation of NP antibiotics from actinomycete bacteria.

scholarly journals Whole genome sequence of Streptomyces humi strain MUSC 119T isolated from intertidal soil

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Hooi-Leng Ser ◽  
Wen-Si Tan ◽  
Wai-Fong Yin ◽  
Kok-Gan Chan ◽  
Nurul Syakima Ab Mutalib ◽  
...  
Keyword(s):  
Gene Clusters ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Species ◽  
Genus Streptomyces ◽  
The Past ◽  
Mangrove Soil ◽  
Natural Product Research ◽  
Biochemical Assays

Over the past few decades, microorganisms have made major contribution in natural product research, particularly those from the genus Streptomyces. Streptomyces humi MUSC 119T was previously isolated as novel streptomycete from mangrove soil in Malaysia. During the screening programme for bioactive strains, this strain was discovered to possess antioxidant activity – scavenging and reducing accumulation of free radicals in biochemical assays. Consequently, whole genome sequencing was performed to evaluate genomic potential of the strain. Based on our analysis, the genome size of MUSC 119T is described to be 10.01 Mbps with G + C content of 71.80%. Based on antiSMASH analysis, the strain possess great genomic potential, having nine biosynthetic gene clusters displaying high similarities to known gene clusters. These findings indicates that mangrove Streptomyces species like MUSC 119T may potentially play an important role in drug development process, while the availability of its whole genome sequences allows further manipulation to isolate and identify compound of interest.

scholarly journals Pan-Genome of the Genus Streptomyces and Prioritization of Biosynthetic Gene Clusters With Potential to Produce Antibiotic Compounds

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Caicedo-Montoya ◽  
Monserrat Manzo-Ruiz ◽  
Rigoberto Ríos-Estepa
Keyword(s):  
Comparative Genomics ◽  
Sequence Similarity ◽  
Experimental Studies ◽  
Gene Clusters ◽  
Antibiotic Activity ◽  
Genomic Diversity ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genus Streptomyces ◽  
Pan Genome

Species of the genus Streptomyces are known for their ability to produce multiple secondary metabolites; their genomes have been extensively explored to discover new bioactive compounds. The richness of genomic data currently available allows filtering for high quality genomes, which in turn permits reliable comparative genomics studies and an improved prediction of biosynthetic gene clusters (BGCs) through genome mining approaches. In this work, we used 121 genome sequences of the genus Streptomyces in a comparative genomics study with the aim of estimating the genomic diversity by protein domains content, sequence similarity of proteins and conservation of Intergenic Regions (IGRs). We also searched for BGCs but prioritizing those with potential antibiotic activity. Our analysis revealed that the pan-genome of the genus Streptomyces is clearly open, with a high quantity of unique gene families across the different species and that the IGRs are rarely conserved. We also described the phylogenetic relationships of the analyzed genomes using multiple markers, obtaining a trustworthy tree whose relationships were further validated by Average Nucleotide Identity (ANI) calculations. Finally, 33 biosynthetic gene clusters were detected to have potential antibiotic activity and a predicted mode of action, which might serve up as a guide to formulation of related experimental studies.

scholarly journals A global survey of specialized metabolic diversity encoded in bacterial genomes

2021 ◽  
Author(s):  
Athina Gavriilidou ◽  
Satria A Kautsar ◽  
Nestor Zaburannyi ◽  
Daniel Krug ◽  
Rolf Mueller ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Evolutionary History ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Metabolic Diversity ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Taxonomic Rank ◽  
New Antibiotics ◽  
Biosynthetic Machinery

Bacterial secondary metabolites have been studied for decades for their usefulness as drugs, such as antibiotics. However, the identification of new structures has been decelerating, in part due to rediscovery of known compounds. Meanwhile, multi-resistant pathogens continue to emerge, urging the need for new antibiotics. It is unclear how much chemical diversity exists in Nature and whether discovery efforts should be focused on established antibiotic producers or rather on understudied taxa. Here, we surveyed around 170,000 bacterial genomes as well as several thousands of Metagenome Assembled Genomes (MAGs) for their diversity in Biosynthetic Gene Clusters (BGCs) known to encode the biosynthetic machinery for producing secondary metabolites. We used two distinct algorithms to provide a global overview of the biosynthetic diversity present in the sequenced part of the bacterial kingdom. Our results indicate that only 3% of genomic potential for natural products has been experimentally discovered. We connect the emergence of most biosynthetic diversity in evolutionary history close to the taxonomic rank of genus. Despite enormous differences in potential among taxa, we identify Streptomyces as by far the most biosynthetically diverse based on currently available data. Simultaneously, our analysis highlights multiple promising high-producing taxas that have thus far escaped investigation.

scholarly journals Discovery and Heterologous Production of New Cyclic Depsibosamycins

2021 ◽  
Vol 9 (7) ◽  
pp. 1396
Author(s):  
Marc Stierhof ◽  
Maksym Myronovskyi ◽  
Josef Zapp ◽  
Andriy Luzhetskyy
Keyword(s):  
Cyclic Peptides ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Side Chain ◽  
Biological Functions ◽  
Biosynthetic Gene Clusters ◽  
Streptomyces Species ◽  
Peptide Synthetases ◽  
Major Interest ◽  
In Silico Identification

Streptomyces are producers of valuable secondary metabolites with unique scaffolds that perform a plethora of biological functions. Nonribosomal peptides are of special interest due to their variety and complexity. They are synthesized by nonribosomal peptide synthetases, large biosynthetic machineries that are encoded in the genome of many Streptomyces species. The identification of new peptides and the corresponding biosynthetic gene clusters is of major interest since knowledge can be used to facilitate combinatorial biosynthesis and chemical semisynthesis of natural products. The recently discovered bosamycins are linear octapeptides with an interesting 5-OMe tyrosine moiety and various modifications at the N-terminus. In this study, the new cyclic depsibosamycins B, C, and D from Streptomyces aurantiacus LU19075 were discovered. In comparison to the linear bosamycins B, C, and D, which were also produced by the strain, the cyclic depsibosamycins showed a side-chain-to-tail lactonization of serine and glycine, leading to a ring of four amino acids. In silico identification and heterologous expression of the depsibosamycin (dbm) gene cluster indicated that the cyclic peptides, rather than the linear derivatives, are the main products of the cluster.

scholarly journals Antiplasmodial activity, biosynthetic gene clusters diversity, and secondary metabolite constituent of selected Indonesian Streptomyces

2021 ◽  
Vol 22 (6) ◽  
Author(s):  
Ema Damayanti ◽  
Puspita Lisdiyanti ◽  
Andini Sundowo ◽  
Shanti Ratnakomala ◽  
Achmad Dinoto ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Ethyl Acetate ◽  
Secondary Metabolite ◽  
Molecular Identification ◽  
Gene Clusters ◽  
Antiplasmodial Activity ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genus Streptomyces ◽  
Rdna Sequencing

Abstract. Damayanti E, Lisdiyanti P, Sundowo A, Ratnakomala S, Dinoto A, Widada J, Mustofa. 2021. Antiplasmodial activity, biosynthetic gene clusters diversity, and secondary metabolite constituent of selected Indonesian Streptomyces. Biodiversitas 22: 3478-3487. Actinobacteria of the genus Streptomyces are known as the primary candidate antibiotics, but still limited for antiplasmodial drugs. This study aimed to investigate the antiplasmodial activity, the biosynthetic gene clusters (BGCs) diversity, and the secondary metabolites constituent of selected Indonesian Streptomyces. The bacteria were isolated from various habitats: karst soil (GMR22), mangrove sediments (BSE7F and SHP 22-7), and marine sediment (GMY01). Molecular identification by 16S rDNA sequencing were performed for confirmation and morphological characterization by scanning electron microscope (SEM) were performed for identification. In vitro antiplasmodial assay was performed on human Plasmodium falciparum FCR-3. The BGCs which encode secondary metabolites were analysed using antiSMASH version 5 based on available whole genome sequence (WGS) data. The secondary metabolites were obtained from liquid fermentation followed by extraction using methanol and ethyl acetate. The secondary metabolites constituent was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). The molecular identification showed that GMR22 had similarity to Streptomyces lactacystinicus (98.02%), while BSE7F was similar to Streptomyces althioticus (97.06%), SHP 22-7 was similar to Streptomyces rochei (94.84%), and GMY01 to Streptomyces odonnellii (98.57%). All of isolates had morphological characteristics as the genus Streptomyces bacteria. The highest Plasmodium inhibition (81.84 ± 3.5%) was demonstrated by ethyl acetate extract of marine-derived Streptomyces sp. GMY01 (12.5 µg/mL). Non-ribosomal polyketide synthetase (NRPS), polyketide synthase (PKS) and hybrid of NRPS-PKS were the major BGCs in all Streptomyces. Majority of the Streptomyces produced compounds containing CHON elements with molecular weight approximately 100-400 Da. The active extract of GMY01 bacterium had five major detected compounds, namely kuraramine (C12H18N2O2), laminine (C9H20N2O2) 2-ethylacetanilide (C10H13NO), propoxur (C11H15NO3), and 3-methyl-1,2-diphenylbutan-1-one (C17H18O). This Indonesian marine bacterium is potential for bioassay guided isolation of antiplasmodial compounds in the future studies.

The Internet and Representative Democracy

2012 ◽  
pp. 362-379
Author(s):  
Giovanni Navarria
Keyword(s):  
New Technologies ◽  
Positive Element ◽  
The Internet ◽  
The Road ◽  
On The Road ◽  
Democratic Systems ◽  
The One ◽  
Representative System ◽  
The Uk ◽  
New Generation

The chapter questions a conventional line of interpretation of the political relevance of the Internet in democratic countries: if on the one hand new communication media such as the Internet represent a positive element in the fight against the hubris of power; on the other hand, the same technologies can serve the agenda of those who want to influence popular consent in support of questionable politics and, hence, hinder the representative system in its very essence. To elucidate this point, the chapter focuses on the Road Tax online-petition that in the early months of 2007 attracted almost 2 million signatures on the UK Government e-Petition website. My argument here is that when simple and historical democratic means such as petitions are coupled with the new generation of Web technologies, the outcome might be unexpected. The road-tax petition will serve us as a blueprint of: the possibilities embedded in the use of new technologies within representative democratic systems, the challenges they pose for democracy, and their unforeseen consequences.

scholarly journals A Glossary for Chemical Approaches towards Unlocking the Trove of Metabolic Treasures in Actinomycetes

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 142
Author(s):  
Jianye Zhang ◽  
Heba Ali Hassan ◽  
Usama Ramadan Abdelmohsen ◽  
Eman Maher Zahran
Keyword(s):  
Secondary Metabolites ◽  
Gene Clusters ◽  
Physiological Signals ◽  
Genomic Sequencing ◽  
Biosynthetic Gene ◽  
Chemical Signaling ◽  
Sequencing Data ◽  
Biosynthetic Gene Clusters ◽  
New Antibiotics ◽  
New Metabolites

Actinobacterial natural products showed a critical basis for the discovery of new antibiotics as well as other lead secondary metabolites. Varied environmental and physiological signals touch the antibiotic machinery that faced a serious decline in the last decades. The reason was exposed by genomic sequencing data, which revealed that Actinomycetes harbor a large portion of silent biosynthetic gene clusters in their genomes that encrypt for secondary metabolites. These gene clusters are linked with a great reservoir of yet unknown molecules, and arranging them is considered a major challenge for biotechnology approaches. In the present paper, we discuss the recent strategies that have been taken to augment the yield of secondary metabolites via awakening these cryptic genes in Actinomycetes with emphasis on chemical signaling molecules used to induce the antibiotics biosynthesis. The rationale, types, applications and mechanisms are discussed in detail, to reveal the productive path for the unearthing of new metabolites, covering the literature until the end of 2020.

scholarly journals Stress-induced formation of cell wall-deficient cells in filamentous actinomycetes

2016 ◽  
Author(s):  
K. Ramijan ◽  
E. Ultee ◽  
J. Willemse ◽  
A.J. Wondergem ◽  
D. Heinrich ◽  
...  
Keyword(s):  
Cell Wall ◽  
Prolonged Exposure ◽  
Gene Clusters ◽  
Adaptation Strategy ◽  
Hyperosmotic Stress ◽  
Cell Type ◽  
Biosynthetic Gene Clusters ◽  
Resistance Determinants ◽  
A Cell ◽  
Almost All

ABSTRACTThe cell wall is a shape-defining structure that envelopes almost all bacteria. One of its main functions is to serve as a protection barrier to environmental stresses. Bacteria can be forced in a cell wall-deficient state under highly specialized conditions, which are invariably aimed at interrupting cell wall synthesis. Therefore, the relevance of such cells has remained obscure. Here we show that many filamentous actinomycetes have a natural ability to generate a new, cell wall-deficient cell type in response to hyperosmotic stress, which we call S-cells. This wall-deficient state is transient, as S-cells are able to switch to the canonical mycelial mode-of-growth. Remarkably, prolonged exposure of S-cells to hyperosmotic stress yielded variants that are able to proliferate indefinitely without their cell wall. This is the first report that demonstrates the formation of wall-deficient cells as a natural adaptation strategy and their potential transition into stable wall-less forms solely caused by prolonged exposure to osmotic stress. Given that actinomycetes are potent antibiotic producers, our work also provides important insights into how biosynthetic gene clusters and resistance determinants may disseminate into the environment.

scholarly journals Genome Sequencing of Streptomyces olivaceus SCSIO T05 and Activated Production of Lobophorin CR4 via Metabolic Engineering and Genome Mining

Marine Drugs ◽  
2019 ◽  
Vol 17 (10) ◽  
pp. 593 ◽  
Author(s):  
Chunyan Zhang ◽  
Wenjuan Ding ◽  
Xiangjing Qin ◽  
Jianhua Ju
Keyword(s):  
Metabolic Engineering ◽  
Deep Sea ◽  
Genome Mining ◽  
Gene Clusters ◽  
Type I ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Genus Streptomyces ◽  
Disruption Method ◽  
Streptomyces Olivaceus

Marine-sourced actinomycete genus Streptomyces continues to be an important source of new natural products. Here we report the complete genome sequence of deep-sea-derived Streptomyces olivaceus SCSIO T05, harboring 37 putative biosynthetic gene clusters (BGCs). A cryptic BGC for type I polyketides was activated by metabolic engineering methods, enabling the discovery of a known compound, lobophorin CR4 (1). Genome mining yielded a putative lobophorin BGC (lbp) that missed the functional FAD-dependent oxidoreductase to generate the d-kijanose, leading to the production of lobophorin CR4 without the attachment of d-kijanose to C17-OH. Using the gene-disruption method, we confirmed that the lbp BGC accounts for lobophorin biosynthesis. We conclude that metabolic engineering and genome mining provide an effective approach to activate cryptic BGCs.

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