Covering: 2006 to 2017
Actinomycetes have been, for decades, one of the most important sources for the discovery of new antibiotics with an important number of drugs and analogs successfully ...introduced in the market and still used today in clinical practice. The intensive antibacterial discovery effort that generated the large number of highly potent broad-spectrum antibiotics, has seen a dramatic decline in the large pharma industry in the last two decades resulting in a lack of new classes of antibiotics with novel mechanisms of action reaching the clinic. Whereas the decline in the number of new chemical scaffolds and the rediscovery problem of old known molecules has become a hurdle for industrial natural products discovery programs, new actinomycetes compounds and leads have continued to be discovered and developed to the preclinical stages. Actinomycetes are still one of the most important sources of chemical diversity and a reservoir to mine for novel structures that is requiring the integration of diverse disciplines. These can range from novel strategies to isolate species previously not cultivated, innovative whole cell screening approaches and on-site analytical detection and dereplication tools for novel compounds, to
in silico
biosynthetic predictions from whole gene sequences and novel engineered heterologous expression, that have inspired the isolation of new NPs and shown their potential application in the discovery of novel antibiotics. This review will address the discovery of antibiotics from actinomycetes from two different perspectives including: (1) an update of the most important antibiotics that have only reached the clinical development in the recent years despite their early discovery, and (2) an overview of the most recent classes of antibiotics described from 2006 to 2017 in the framework of the different strategies employed to untap novel compounds previously overlooked with traditional approaches.
An update on last ten years of actinomycetes antibiotic discovery, including recent key molecules in clinical development and overlooked compounds discovered using novel strategies.
New classes of antibacterial compounds are urgently needed to respond to the high frequency of occurrence of resistances to all major classes of known antibiotics. Microbial natural products have ...been for decades one of the most successful sources of drugs to treat infectious diseases but today, the emerging unmet clinical need poses completely new challenges to the discovery of novel candidates with the desired properties to be developed as antibiotics. While natural products discovery programs have been gradually abandoned by the big pharma, smaller biotechnology companies and research organizations are taking over the lead in the discovery of novel antibacterials. Recent years have seen new approaches and technologies being developed and integrated in a multidisciplinary effort to further exploit microbial resources and their biosynthetic potential as an untapped source of novel molecules. New strategies to isolate novel species thought to be uncultivable, and synthetic biology approaches ranging from genome mining of microbial strains for cryptic biosynthetic pathways to their heterologous expression have been emerging in combination with high throughput sequencing platforms, integrated bioinformatic analysis, and on-site analytical detection and dereplication tools for novel compounds. These different innovative approaches are defining a completely new framework that is setting the bases for the future discovery of novel chemical scaffolds that should foster a renewed interest in the identification of novel classes of natural product antibiotics from the microbial world.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The current spread of multi-drug resistance in a number of key pathogens and the lack of therapeutic solutions in development to address most of the emerging infections in the clinic that are ...difficult to treat have become major concerns. Microbial natural products represent one of the most important sources for the discovery of potential new antibiotics and actinomycetes have been one of the most relevant groups that are prolific producers of these bioactive compounds. Advances in genome sequencing and bioinformatic tools have collected a wealth of knowledge on the biosynthesis of these molecules. This has revealed the broad untapped biosynthetic diversity of actinomycetes, with large genomes and the capacity to produce more molecules than previously estimated, opening new opportunities to identify the novel classes of compounds that are awaiting to be discovered. Comparative genomics, metabolomics and proteomics and the development of new analysis and genetic engineering tools provide access to the integration of new knowledge and better understanding of the physiology of actinomycetes and their tight regulation of the production of natural products antibiotics. This new paradigm is fostering the development of new genomic-driven and culture-based strategies, which aims to deliver new chemical classes of antibiotics to be developed to the clinic and replenish the exhausted pipeline of drugs for fighting the progression of infection diseases in the near future.
Microbial natural products have been one of the most important sources for the discovery of potential new antibiotics. However, the decline in the number of new chemical scaffolds discovered and the ...rediscovery problem of old known molecules has become a limitation for discovery programs developed by an industry confronted by a lack of incentives and a broken economic model. In contrast, the emergence of multidrug resistance in key pathogens has continued to progress and this issue is compounded by a lack of new antibiotics in development to address most of the difficult to treat infections.
Advances in genome mining have confirmed the richness of biosynthetic gene clusters (BGCs) in the majority of microbial sources, and this suggests that an untapped chemical diversity is waiting to be discovered. The development of new genome engineering and synthetic biology tools, and the implementation of comparative omic approaches is fostering the development of new integrated culture-based strategies and genomic-driven approaches aimed at delivering new chemical classes of antibiotics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current ...level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
Streptomycetes are major producers of bioactive natural products, including the majority of the naturally produced antibiotics. While much of the low-hanging fruit has been discovered, it is ...predicted that less than 5% of the chemical space of natural products has been mined. Here, we describe the discovery of the novel actinomycins L
and L
produced by Streptomyces sp. MBT27, via application of metabolic analysis and molecular networking. Actinomycins L
and L
are diastereomers, and the structure of actinomycin L
was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X
prior to the condensation of the actinomycin halves. Such a structural feature has not previously been identified in naturally occurring actinomycins. Adding anthranilamide to cultures of the actinomycin X
producer Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27, resulted in the production of actinomycin L. This supports a biosynthetic pathway whereby actinomycin L is produced from two distinct metabolic routes, namely those for actinomycin X
and for anthranilamide. Actinomycins L
and L
showed significant antimicrobial activity against Gram-positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cacaoidin, First Member of the New Lanthidin RiPP Family Ortiz‐López, Francisco Javier; Carretero‐Molina, Daniel; Sánchez‐Hidalgo, Marina ...
Angewandte Chemie International Edition,
July 27, 2020, Volume:
59, Issue:
31
Journal Article
Peer reviewed
Lantibiotics are ribosomally synthesized and post‐translationally modified peptides (RiPPs) characterized by the presence of lanthionine or methyllanthionine rings and their antimicrobial activity. ...Cacaoidin, a novel glycosylated lantibiotic, was isolated from a Streptomyces cacaoi strain and fully characterized by NMR, mass spectrometry, chemical derivatization approaches and genome analysis. The new molecule combines outstanding structural features, such as a high number of d‐amino acids, an uncommon glycosylated tyrosine residue and an unprecedented N,N‐dimethyl lanthionine. This latter feature places cacaoidin within a new RiPP family located between lanthipeptides and linaridins, here termed lanthidins. Cacaoidin displayed potent antibacterial activity against Gram‐positive pathogens including Clostridium difficile. The biosynthetic gene cluster showed low homology with those of other known lanthipeptides or linaridins, suggesting a new RiPP biosynthetic pathway.
Lanthidins: A novel glycosylated lantibiotic, cacaoidin, inaugurates a new RiPP family characterized by the co‐occurrence of lanthionine rings and N‐terminus dimethylation, structural features both restricted to the lanthipeptide and linaridin RiPP families, respectively. Cacaoidin combines both elements in an unprecedented N,N‐dimethyl lanthionine system and exhibits a rare tyrosine‐O‐glycosylated residue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
As part of our screening program for the discovery of molecules of microbial origin with skin-whitening activity, 142 diverse fungal endophytes from a wide variety of Andalusia arid plants were ...screened, applying the OSMAC approach. The fungal strains CF-090361 and CF-090766, isolated from xerophytic plants, were selected as the most promising, while phylogenetic analysis revealed that both strains could represent a new species within the genus Comoclathris. The effect of different fermentation conditions on the production of tyrosinase inhibitory activity was examined, in order to identify the optimum cultivation conditions. LCMS based metabolomics was applied to determine significant differences between the strains and fermentation conditions, and to identify potential bioactive secondary metabolites. Bioassay-guided purification of the main active components led to the isolation of three new compounds (1-3), along with the known compounds graphostrin B (4) and brevianamide M (5). Compound 1 (Comoclathrin) demonstrated the strongest anti-tyrosinase activity (IC
0.16 μΜ), which was 90-times higher than kojic acid (IC
14.07 μΜ) used as positive control. Additionally, comoclathrin showed no significant cytotoxicity against a panel of cancer cell lines (HepG2, A2058, A549, MCF-7 and MIA PaCa-2) and normal BJ fibroblasts. These properties render comoclathrin an excellent development candidate as whitening agent.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A novel chemo-organoheterotroph bacterium, strain CB-286315T, was isolated from a Mediterranean forest soil sampled at the Sierra de Tejeda, Almijara and Alhama Natural Park, Spain, by using the ...diffusion sandwich system, a device with 384 miniature diffusion chambers. 16S rRNA gene sequence analyses identified the isolate as a member of the under-represented phylum Gemmatimonadetes, where 'Gemmatirosa kalamazoonensis' KBS708, Gemmatimonas aurantiaca T-27T and Gemmatimonas phototrophica AP64T were the closest relatives, with respective similarities of 84.4, 83.6 and 83.3 %. Strain CB-286315T was characterized as a Gram-negative, non-motile, short to long rod-shaped bacterium. Occasionally, some cells attained an unusual length, up to 35-40 μm. The strain showed positive responses for catalase and cytochrome-c oxidase and division by binary fission, and exhibited an aerobic metabolism, showing optimal growth under normal atmospheric conditions. Strain CB-286315T was also able to grow under micro-oxic atmospheres, but not under anoxic conditions. The strain is a slowly growing bacterium able to grow under low nutrient concentrations. Major fatty acids included iso-C17 : 1ω9c, summed feature 3 (C16 : 1ω7c and/or iso-C15 : 0 2-OH), C16 : 0 and iso-C17 : 0. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified glycolipids and three phospholipids. The major isoprenoid quinone was MK-8 and the diagnostic diamino acid was meso-diaminopimelic acid. The DNA G+C content was 67.0 mol%. Based on a polyphasic taxonomic characterization, strain CB-286315T represents a novel genus and species, Longimicrobium terrae gen. nov., sp. nov., within the phylum Gemmatimonadetes. The type strain of Longimicrobium terrae is strain CB-286315T ( = DSM 29007T = CECT 8660T). In order to classify the novel taxon within the existing taxonomic framework, the family Longimicrobiaceae fam. nov., order Longimicrobiales ord. nov. and class Longimicrobia classis nov. are also proposed.
Lanthipeptides are ribosomally synthesized and post-translationally modified peptides characterized by lanthionine (Lan) and/or methyllanthionine (MeLan) residues. Four classes of enzymes have been ...identified to install these structures in a substrate peptide. Recently, a novel class of lanthipeptides was discovered that lack genes for known class I–IV lanthionine synthases in their biosynthetic gene cluster (BGC). In this study, the dehydration of Ser/Thr during the biosynthesis of the class V lanthipeptide cacaoidin was reconstituted in vitro. The aminoglycoside phosphotransferase-like enzyme CaoK iteratively phosphorylates Ser/Thr residues on the precursor peptide CaoA, followed by phosphate elimination catalyzed by the HopA1 effector-like protein CaoY to achieve eight successive dehydrations. CaoY shows sequence similarity to the OspF family proteins and the lyase domains of class III/IV lanthionine synthetases, and mutagenesis studies identified residues that are critical for catalysis. An AlphaFold prediction of the structure of the dehydration enzyme complex engaged with its substrate suggests the importance of hydrophobic interactions between the CaoA leader peptide and CaoK in enzyme–substrate recognition. This model is supported by site-directed mutagenesis studies.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
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