Oxytetracycline is a broad-spectrum tetracycline antibiotic, the second of the group to be discovered.
In organic chemistry, polyketides are a class of natural products derived from a precursor molecule consisting of a chain of alternating ketone and methylene groups: [−C(=O)−CH2−]n. First studied in the early 20th century, discovery, biosynthesis, and application of polyketides has evolved. It is a large and diverse group of secondary metabolites caused by its complex biosynthesis which resembles that of fatty acid synthesis. Because of this diversity, polyketides can have various medicinal, agricultural, and industrial applications. Many polyketides are medicinal or exhibit acute toxicity. Biotechnology has enabled discovery of more naturally-occurring polyketides and evolution of new polyketides with novel or improved bioactivity.
Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
Neocarzinostatin (NCS) is a macromolecular chromoprotein enediyne antitumor antibiotic secreted by Streptomyces macromomyceticus.
Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. In contrast, only one known non-wild type species, streptomyces peucetius subspecies caesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin. His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. This is of more than academic interest because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum. More efficient production techniques have brought the price down to $1.1 million per kg for the non-liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.
Streptogramin A is a group of antibiotics within the larger family of antibiotics known as streptogramins. They are synthesized by the bacteria Streptomyces virginiae. The streptogramin family of antibiotics consists of two distinct groups: group A antibiotics contain a 23-membered unsaturated ring with lactone and peptide bonds while group B antibiotics are depsipeptides. While structurally different, these two groups of antibiotics act synergistically, providing greater antibiotic activity than the combined activity of the separate components. These antibiotics have until recently been commercially manufactured as feed additives in agriculture, although today there is increased interest in their ability to combat antibiotic-resistant bacteria, particularly vancomycin-resistant bacteria.
Nogalamycin is an anthracycline antibiotic produced by the soil bacteria Streptomyces nogalater. It has antitumor properties but it is also highly cardiotoxic. The less cardiotoxic semisynthetic analog menogaril was developed in the 1970s. Currently nogalamycin and menogaril are not used clinically.
Pikromycin was studied by Brokmann and Hekel in 1951 and was the first antibiotic macrolide to be isolated. Pikromycin is synthesized through a type I polyketide synthase system in Streptomyces venezuelae, a species of Gram-positive bacterium in the genus Streptomyces. Pikromycin is derived from narbonolide, a 14-membered ring macrolide. Along with the narbonolide backbone, pikromycin includes a desosamine sugar and a hydroxyl group. Although Pikromycin is not a clinically useful antibiotic, it can be used as a raw material to synthesize antibiotic ketolide compounds such as ertythromycins and new epothilones.
Farinamycin is a quinazoline metabolite that has been isolated from Streptomyces griseus. It is the first known metabolite to be produced by S. griseus that is not a phenoxazinone antibiotic. Farinamycin is formed from the condensation of 3-OH-anthranalite and 3,4-AHBA building blocks that later combine with Enaminomycin C biosynthetically. Many Streptomyces natural products have been used as antibiotics, antifungals, anticancer agents and immunosuppressive agents.
Pseurotin A is a secondary metabolite of Aspergillus.
Atrop-abyssomicin C is a polycyclic polyketide-type natural product that is the atropisomer of abyssomicin C. It is a spirotetronate that belongs to the class of tetronate antibiotics, which includes compounds such as tetronomycin, agglomerin, and chlorothricin. In 2006, the Nicolaou group discovered atrop-abyssomicin C while working on the total synthesis of abyssomicin C. Then in 2007, Süssmuth and co-workers isolated atrop-abyssomicin C from Verrucosispora maris AB-18-032, a marine actinomycete found in sediment of the Japanese sea. They found that atrop-abyssomicin C was the major metabolite produced by this strain, while abyssomicin C was a minor product. The molecule displays antibacterial activity by inhibiting the enzyme PabB, thereby depleting the biosynthesis of p-aminobenzoate.
Streptomyces thioluteus is a bacterium species from the genus of Streptomyces. Streptomyces thioluteus produces leupeptins, phenazines, phenoxazinones, dioxopiperazines, questiomycin A, aureothricin and aureothin.
A jadomycin is a natural product produced by Streptomyces venezuelae ISP5230 (ATCC10712), the organism which is most well known for making the antibiotic chloramphenicol. The name jadomycin is applied to a family of related angucyclines which are distinguished by the E ring, which is derived from an amino acid. The amino acid incorporation which forms the E-ring is a chemical reaction, rather than enzymatic, an uncommon occurrence in biosynthesis. As such a number of jadomycins incorporating different amino acids have been discovered. Jadomycin A was the first compound of this family to be isolated and constitutes the angucylic backbone with L-isoleucine incorporated into the E-ring. A related analog, jadomycin B, is modified by glycosylation with a 2,6-dideoxy sugar, L-digitoxose. Jadomycins have cytotoxic and antibacterial properties.
C-1027 or lidamycin is an antitumor antibiotic consisting of a complex of an enediyne chromophore and an apoprotein. It shows antibiotic activity against most Gram-positive bacteria. It is one of the most potent cytotoxic molecules known, due to its induction of a higher ratio of DNA double-strand breaks than single-strand breaks.
Borrelidin is an 18-membered polyketide macrolide derived from several Streptomyces species. First discovered in 1949 from Streptomyces rochei, Borrelidin shows antibacterial activity by acting as an inhibitor of threonyl-tRNA synthetase and features a nitrile moiety, a unique functionality in natural products., Borrelidin also exhibits potent angiogenesis inhibition, which was shown in a rat aorta matrix model. Other studies have been performed to show that low concentrations of borrelidin can suppress growth and induce apoptosis in malignant acute lymphoblastic leukemia cells. Borredlidin's antimalarial activity has also been shown in vitro and in vivo.
Pyoluteorin is a natural antibiotic that is biosynthesized from a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway. Pyoluteorin was first isolated in the 1950s from Pseudomonas aeruginosa strains T359 and IFO 3455 and was found to be toxic against oomycetes, bacteria, fungi, and against certain plants. Pyoluteorin is most notable for its toxicity against the oomycete Pythium ultimum, which is a plant pathogen that causes a global loss in agriculture. Currently, pyoluteorin derivatives are being studied as an Mcl-1 antagonist in order to target cancers that have elevated Mcl-1 levels.
Annimycin (4-(Z)-annimycin) is a polyenoic acid amide natural product produced by Streptomyces calvus. Annimycin inhibits the sporulation of several actinobacterial genera.
Butyrolactol A is an organic chemical compound of interest for its potential use as an antifungal antibiotic.
Tylactone synthase or TYLS is a Type 1 polyketide synthase. TYLS is found in strains of Streptomyces fradiae and responsible for the synthesis of the macrolide ring, tylactone, the precursor of an antibiotic, tylosin. TYLS is composed of five large multi-functional proteins, TylGI-V. Each protein contains either one or two modules. Each module consists of a minimum of a Ketosynthase (KS), an Acyltransferase (AT), and an Acyl carrier protein (ACP) but may also contain a Ketoreductase (KR), Dehydrotase (DH), and Enoyl Reductase (ER) for additional reduction reactions. The domains of TYLS have similar activity domains to those found in other Type I polyketide synthase such as 6-Deoxyerythronolide B synthase (DEBS). The TYLS system also contains a loading module consisting of a ketosynthase‐like decarboxylase domain, an acyltransferase, and acyl carrier protein. The terminal Thioesterase terminates tylactone synthesis by cyclizing the macrolide ring. After the TYLS completes tylactone synthesis, the tylactone molecule is modified by oxidation at C-20 and C-23 and glycosylation of mycaminose, mycinose, and mycarose to produce tylosin.
Prescopranone is a key intermediate in the biosynthesis of scopranones. Prescopranone is the precursor to scopranone A, scopranone B, and scopranone C, which are produced by Streptomyces sp. BYK-11038.
