The myxobacteria are a group of bacteria that predominantly live in the soil and feed on insoluble organic substances. The myxobacteria have very large genomes relative to other bacteria, e.g. 9–10 million nucleotides except for Anaeromyxobacter and Vulgatibacter. One species of myxobacteria, Minicystis rosea, has the largest known bacterial genome with over 16 million nucleotides. The second largest is another myxobacteria Sorangium cellulosum.
The rifamycins are a group of antibiotics that are synthesized either naturally by the bacterium Amycolatopsis rifamycinica or artificially. They are a subclass of the larger family of ansamycins. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.
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.
Myxococcus xanthus is a gram-negative, bacillus species of myxobacteria that exhibits various forms of self-organizing behavior in response to environmental cues. Under normal conditions with abundant food, it exists as a predatory, saprophytic single-species biofilm called a swarm. Under starvation conditions, it undergoes a multicellular development cycle.
Sorangium cellulosum is a soil-dwelling Gram-negative bacterium of the group myxobacteria. It is motile and shows gliding motility. Under stressful conditions this motility, as in other myxobacteria, the cells congregate to form fruiting bodies and differentiate into myxospores. These congregating cells make isolation of pure culture and colony counts on agar medium difficult as the bacterium spread and colonies merge. It has an unusually-large genome of 13,033,779 base pairs, making it the largest bacterial genome sequenced to date by roughly 4 Mb.
Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis.
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).
Stigmatella aurantiaca is a member of myxobacteria, a group of gram-negative bacteria with a complex developmental life cycle.
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).
Salinispora is a genus of obligately aerobic, gram-positive, non-acid-fast bacteria belonging to the family of Micromonosporaceae. They are heterotrophic, non-motile, and obligately grow under high osmotic/ionic-strength conditions. They are the first identified genus of gram-positive bacteria which has a high osmotic/ionic-strength requirement for survival. They are widely abundant in tropical marine sediments and were first identified in 2002. This genus of bacteria has potential biotechnological significance due to their production of novel secondary metabolites which can be used pharmaceutically.
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.
Curacin A is a hybrid polyketide synthase (PKS)/nonribosomal peptide synthase (NRPS) derived natural product produced isolated from the cyanobacterium Lyngbya majuscula. Curacin A belongs to a family of natural products including jamaicamide, mupirocin, and pederin that have an unusual terminal alkene. Additionally, Curacin A contains a notable thiazoline ring and a unique cyclopropyl moiety, which is essential to the compound's biological activity. Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer. Curacin A has been shown to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation.
Streptomyces arenae is a bacterium species from the genus Streptomyces which has been isolated from soil from Illinois in the United States. Streptomyces arenae produces pentalenolactone, 2,5-dihydrophenylalanine, naphthocyclinone and arenaemycine.
Gephyronic acid is a polyketide that exists as an equilibrating mixture of structural isomers. In nature, gephyronic acid is produced by slow growing myxobacterium: Archangium gephyra strain Ar3895 and Cystobacter violaceus strain Cb vi76. It is the first antibiotic in myxobacteria that was reported to specifically inhibit eukaryotic protein synthesis.
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.
Plesiocystis pacifica is a species of marine myxobacteria. Like other members of this order, P. pacifica is a rod-shaped Gram-negative bacterium that can move by gliding and can form aggregates of cells called fruiting bodies. The species was first described in 2003, based on two strains isolated from samples collected from the Pacific coast of Japan.
Plesiocystis is a genus of myxobacteria. It is a monotypic taxon containing only its type species, Plesiocystis pacifica. Both the genus and the species were first described in 2003, based on two strains isolated from samples collected from the Pacific coast of Japan.
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.
Chlorotonil A is a polyketide natural product produced by the myxobacterium Sorangium cellulosum So ce1525. It displays antimalarial activity in an animal model, and has in vitro antibacterial and antifungal activity. The activity of chlorotonil A has been attributed to the gem-dichloro-1,3-dione moiety, which is a unique functionality in polyketides. In addition to its unique halogenation, the structure of chlorotonil A has also garnered interest due to its similarity to anthracimycin, a polyketide natural product with antibiotic activity against Gram-positive bacteria.
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.
