Streptomyces avermitilis

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A Microbial Biorealm page on the genus Streptomyces avermitilis


Classification

Bacteria; Actinobacteria; Actinobacteridae; Actinomycetales; Streptomycineae; Streptomycetaceae; Streptomyces; Streptomyces avermitilis

Species

NCBI: Taxonomy

Streptomyces avermitilis

Description and significance

Streptomyces avermitilis was first isolated in 1979 at Kitasato Institute from a soil sample collected at Kawana, Ito City, Shizuoka Prefecture, Japan. It was sent to Merck Sharp & Dohme Research Laboratories for screen testing. (1)

This particular Streptomyces species dwells in terrestrial soils and has a brownish-gray spore mass. The spores are spherical (as opposed to oval) with a smooth spore surface and come in chains of more than 15. The sporophores form spiral side branches on aerial mycelia. (1)

S. avermitilis is an important species to have its genome sequenced because it produces certain secondary metabolites, called avermectins, that have antihelmintic and insecticidal properties. (2)

Genome structure

The chromosome of Streptomyces avermitilis contains over 9 million base pairs (9.02-Mb), putting it at the top as one of the largest bacterial genomes sequenced as of yet. It also has a higher GC content (70.7%) than almost any other organism, making the S. avermitilis chromosome unique in its size and structure (3). This linear chromosome contains 7,574 open reading frames (ORFs), as well as unique terminal-inverted repeats at both ends that bind terminal proteins. Of the 7,574 ORFs, 60.2% (or 4,563) encode funtional proteins and about 35% (or 2,663) cluster into 721 paralogous families. Of these 721, two main gene families are represented -- one relating to membrane-spanning components of ABC transporters, and the other relating to two-component transcriptional regulator systems. These results suggest that at least a third of all S. avermitilis genes may have emerged as a result of gene duplication during evolution (4).

Comparing the genomes of S. avermitilis and S. coelicolor A3(2) revealed a 6.5-Mb highly conserved internal region where all the essential genes are located (SAV1625-7142 in S. avermitilis). This region is structurally similar to other circular bacterial chromosomes, implying that this 6.5-Mb internal region may be the underlying backbone of all Streptomyces chromosomes and may have evolved from an ancestor common to all bacteria with circular chromosomes. Conversely, there are also variable, less conserved regions found near both telomeres. More than half the genes related to secondary metabolism (17 out of 30) were found in subtelomeric regions, while no known essential genes were found there (4).

S. avermitilis also contains the plasmid SAP1. SAP1 has 96 ORFs, 34.4% (or 33) of which encode funtional proteins (4).

Overall, the gene content of S. avermitilis suggests that its genome may have evolved by acquisition of novel gene functions that aided in its adaption to the intense competition, unpredictable fluctuation of nutrients, and extremely variable physical conditions of soil environments (4).

Cell structure and metabolism

One of the unique characteristics of S. avermitilis is its production of antiparasitic secondary metabolites, called avermectins. This production is regulated by several parameters, one of them being glucose metabolism. Avermectin formation is suppressed by the addition of glucose at an early stage of fermentation, but not when glucose is added at a later stage. (5)

Most organisms metabolize glucose rapidly, while S. avermitilis digests glucose slowly. There are two major pathways of glucose metabolism -- the Embden-Meyerhof pathway and the pentose phosphate pathway. Metabolites of glucose are then further metabolized in the tricarboxylic acid cycle. The activities of certain enzymes in these metabolic pathways, such as glucose-6-phosphate dehydrogenase, phosphofructokinase, and citrate synthase, are not effected by higher glucose concentrations. However, the activity of 6-phosphogluconate dehydrogenase, a rate-limiting step in the pentose phosphate pathway, is significantly reduced when glucose is overly present at an early stage. (5)

Since glucose is the best carbon source for avermectin production, the amount of glucose effects the rate of avermectin production, as well as the activity of 6-phosphogluconate dehydrogenase. Though avermectin formation is suppressed by the addition of glucose at an early stage of fermentation, the production rate is restored at a later stage as the activity of 6-phosphogluconate dehydrogenase is also restored. (5)

Ecology

The main contribution of S. avermitilis on the environment is its production of avermectins. Though this anthelmintic compound is useful in medicine for fighting internal and external parasites, it has several environmental risks, as well. Their residues in feces of treated animals have toxic effects on many feces and soil invertebrates. They are also toxic to several terrestrial and avian species (bobwhite quail and mallard duck, for instance). (6)

However, the most sensitive organisms to avermectins are freshwater organisms, such as Bluegill sunfish, rainbow trout, and green unicellular algae to name a few. Controversy about the careful administration and dosage of these anthelmintics when treating infected animals is on the rise since numerous chemicals have been found to bioconcentrate in aquatic organisms. (7)

Pathology

Though harmful or toxic to certain freshwater and soil organisms, S. avermitilis can be used beneficially in human and veterinary medicine. The biosynthesis of anthelmintics (compounds that kill helminths, or parasitic worms) is used by this soil bacteria to kill nearby nematodes as a source of food or simply to eliminate competition for resources. However, this nematocide can also be isolated and used to treat such diseases as Onchocerca volvulus (river blindness), Wuchereria bancrofti (elephantitis), Ascaris lumbricoides (intestinal roundworm), and human scabies. (8)

Scabies, for example, is a major public health problem in many countries, infecting hundreds of millions around the world. The most commonly used scabicide is Lindane, which is a very effective drug, but risks serious toxic neurological effects if misused. Ivermectins, on the other hand, a macrocyclic lactone produced by S. avermitilis, lack activity against bacteria and fungi, do not inhibit protein synthesis, nor are they ionophores. Instead they interfere with neurotransmission in many invertebrates and are thus safer for human use. (9)

Ivermectin has also been used to treat patients with onchocerciasis, also known as African river blindness, by decreasing the prevalence of skin and eye diseases linked to this infection. (10)

Application to Biotechnology

As mentioned in previous sections, S. avermitilis is a very useful microbe in biotechnology. The avermectins synthesized by this bacteria can be used for a variety of things from insecticides for diseased plants to the treatment of farm animals infected with intestinal worms to the alleviation of human scabies or river blindness. Each year, technology improves and scientists are finding more and more ways to utilize all kinds of microbes, including Streptomyces avermitilis.

Current Research

A. Over thousands of years, microorganisms have evolved ways to overcome numerous chemical and environmental challenges, including microbial drugs. There is research being done as to why microbial resistance is inevitable, and what can be done about the potential problem of widespread antibiotic resistant bacteria. Is there a new antibiotic that can overcome these rapidly evolving organisms? (11)

B. A new strategy known as “combinatorial biosynthesis” is being developed in which certain bacterial enzymes are being used to synthesize novel drugs. The bacterial multienzyme polyketide synthases (PKSs) produce a variety of products that have been developed into medicines, such as antibiotics and anticancer agents. Scientists have produced over 200 new polyketides and are continuing to build more. (12)

C. Novel chimeric proteins made of a globin domain fused with a “cofactor free” monooxygenase domain have been identified within the Streptomyces avermitilis genome. The chimeric protein was cloned, expressed, and characterized. The findings suggest novel functional roles of truncated hemoglobins, which might represent a vast class of multipurpose oxygen activating/scavenging proteins whose catalytic action is mediated by the interaction with cofactor free monooxygenases. (13)

References

(1) Burg, R., Miller, B., Baker, E., Birnbaum, J. et. al. "Avermectins, New Family of Potent Anthelmintic Agents: Producing Organism and Fermentation." Antimicrobial Agents and Chemotherapy. March 1979. Vol 15, No 3, p. 361-367.

(2) Demain, A. "Pharmaceutically active secondary metabolites of microorganisms." Appl. Microbiol. Biotechnol. 1999. Vol 52, p. 455-463.

(3) Omura, S., Ikeda, H., Ishikawa, J., Hanamoto, A. "Genome sequence of an industrial microorganism Streptomyces avermitilis: Deducing the ability of producing secondary metabolites." The Kitasato Institute for Life Sciences, Kitasato University, Tokyo. August 2001.

(4) Ikeda, H., Ishikawa, J., Hanamoto, A., Shinose, M. "Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis." Nature Biotechnology. May 2003. Vol 21, p. 526-531.

(5) Ikeda, H., Kotaki, H., Tanaka, H., Omura, S. "Involvement of Glucose Catabolism in Avermectin Production by Streptomyces avermitilis." Antimicrobial Agents and Chemotherapy. February 1988, Vol 32, No 2, p. 282-284.

(6) Kolar, L., Erzen, N. "Veterinary Parasiticides - Are They Posing an Environmental Risk?" Slov Vet Res. May 2006. Vol 43, No 2, p. 85-96.

(7) Heuvel, V., Forbis, A., Halley, B. "Bioconcentration and Depuration of Avermectin B1a in the Bluegill Sunfish." Environmental Toxicology and Chemistry. June 1996. Vol 15, No 12, p. 2263-2266.

(8) Caporale, L. "Chemical Ecology: A View from the Pharmaceutical Industry." Proc. Natl. Acad. Sci. USA. January 1995. Vol 92, p. 75-82.

(9) Conti Diaz, I., Amaro, J. "Treatment of human scabies with oral ivermectin." Rev. Inst. Med. trop. S. Paulo. 1999. Vol 41, No 4, p. 259-261.

(10) Gaisser, S., Kellenberger, L., Kaja, A., Weston, A. "Direct production of invermectin-like drugs after domain exchange in the avermectin polyketide synthase of Streptomyces avermitilis ATCC31272." Org. Biomol. Chem.. 2003. Vol 1, p. 2840-2847.

(11) Wright, G. "The antibiotic resistome: the nexus of chemical and genetic diversity." Nature Reviews Microbiology. March 2007. Vol 5, p. 175-186.

(12) Weissman, K., Leadlay, P. "Combinatorial Biosynthesis of Reduced Polyketides." Nature Reviews Microbiology. December 2005. Vol 3, p. 925-936.

(13) Bonamore, A., Attili, A., Arenghi, F., Catacchio, B. "A novel chimera: The 'truncated hemoglobin-antibiotic monooxygenase' from Streptomyces avermitilis." Gene. 2007. Vol 398, p. 52-61.

Edited by Jennifer Woods, student of Rachel Larsen

Edited by KLB