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.
A23187 is a mobile ion-carrier that forms stable complexes with divalent cations. A23187 is also known as Calcimycin, Calcium Ionophore, Antibiotic A23187 and Calcium Ionophore A23187. It is produced at fermentation of Streptomyceschartreusensis.
Neocarzinostatin (NCS) is a macromolecular chromoprotein enediyne antitumor antibiotic secreted by Streptomyces macromomyceticus.
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.
Saccharopolyspora erythraea is a species of actinomycete bacteria within the genus Saccharopolyspora.
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.
Callystatin A is a polyketide natural product from the leptomycin family of secondary metabolites. It was first isolated in 1997 from the marine sponge Callyspongia truncata which was collected from the Goto Islands in the Nagasaki Prefecture of Japan by the Kobayashi group. Since then its absolute configuration has been elucidated and callystatin A was discovered to have anti-fungal and anti-tumor activities with extreme potency against the human epidermoid carcinoma KB cells (IG50 = 10 pg/ml) and the mouse lymphocytic leukemia Ll210 cells (IG50 = 20 pg/ml).
Anthracimycin is a polyketide antibiotic discovered in 2013. Anthracimycin is derived from marine actinobacteria. In preliminary laboratory research, it has shown activity against Bacillus anthracis, the bacteria that causes anthrax, and against methicillin-resistant Staphylococcus aureus (MRSA).
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.
Gladiolin is a polyketide natural product produced by Burkholderia gladioli BCC0238 which is isolated from sputum of cystic fibrosis patients. It was found to be a novel macrolide antibiotic which presented an activity against Mycobacterium tuberculosis. Gladiolin is structurally much more stable than its analogue etnangien as an efficient myxobacterial RNA polymerase inhibitor due to the lack of highly labile hexaene moiety in gladiolin. The good activity and high stability of gladiolin offers it the potential for further development as an antibiotic against antibiotic-resistant M. tuberculosis.
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.
Fostriecin is a type I polyketide synthase (PKS) derived natural product, originally isolated from the soil bacterium Streptomyces pulveraceus. It belongs to a class of natural products which characteristically contain a phosphate ester, an α,β-unsaturated lactam and a conjugated linear diene or triene chain produced by Streptomyces. This class includes structurally related compounds cytostatin and phoslactomycin. Fostriecin is a known potent and selective inhibitor of protein serine/threonine phosphatases, as well as DNA topoisomerase II. Due to its activity against protein phosphatases PP2A and PP4 which play a vital role in cell growth, cell division, and signal transduction, fostriecin was looked into for its antitumor activity in vivo and showed in vitro activity against leukemia, lung cancer, breast cancer, and ovarian cancer. This activity is thought to be due to PP2A's assumed role in regulating apoptosis of cells by activating cytotoxic T-lymphocytes and natural killer cells involved in tumor surveillance, along with human immunodeficiency virus-1 (HIV-1) transcription and replication.
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.
Butyrolactol A is an organic chemical compound of interest for its potential use as an antifungal antibiotic.
Aureothin is a natural product of a cytotoxic shikimate-polyketide antibiotic with the molecular formula C22H23NO6. Aureothin is produced by the bacterium Streptomyces thioluteus that illustrates antitumor, antifungal, and insecticidal activities and the new aureothin derivatives can be antifungal and antiproliferative. In addition, aureothin, a nitro compound from Streptomyces thioluteus, was indicated to have pesticidal activity against the bean weevil by interfering with mitochondrial respiratory complex II.
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.
Pladienolide B is a natural product produced by bacterial strain, Streptomyces platensis MER-11107, which is a gram-positive bacteria isolated from soil in Japan. Pladienolide B is a molecule of interest due to its potential anti-cancer properties. Its anti-cancer mode of action includes binding to the SF3B complex in the U2 snRNP in the human spliceosome.
Peucemycin is a polyketide produced by Streptomyces peucetius, a Gram-positive filamentous bacteria that also produces the anticancer compounds daunorubicin and doxorubicin. This compound was elucidated from a cryptic biosynthetic gene cluster and is produced under temperature-specific conditions for bacterial growth. Peucemycin has demonstrated bioactivity against growth of S. aureus, P. hauseri, and S. enterica and also is weakly active against cancer cell lines. Peucemycin is biosynthesized through a Type 1 PKS system.
Disorazol, a cyclic polyketide synthesized by the bacterium Sorangium cellulosum So ce12, was first detected and isolated in 1994. Its chemical structure consists of a macrocyclic ring and two oxazole rings. Disorazol A has been demonstrated to exhibit anti-fungi activities, but it was not active against yeasts. In addition, this substance demonstrates potent anti-cancer characteristics at exceptionally low picomolar levels by obstructing the mechanism of tubulin assembly and triggering the disruption of microtubules. As a result, these impacts lead to the initiation of cell apoptosis. However, disorazols cannot be directly used as drugs in the clinic due to its extremely high cytotoxicity and instability. Thus, chemical and biosynthetic synthesis pathways were designed to synthesize unnatural derivatives of disorazol in hope of reducing its cytotoxicity without decreasing its anti-cancer potency.
