Microbial Biotechnology: Scope, Techniques, Examples Continued..

SECONDARY METABOLITES AS A SOURCE OF DRUGS:
Microorganisms produce a huge number of small molecular weight compounds that are broadly described as secondary metabolites. A traditional
approach to the discovery of new, naturally occurring bio active molecules
utilizes “screens.” A screen is an assay procedure that allows testing of numerous compounds for a particular activity. Tens of thousands of secondary
metabolites and other compounds have been examined for biological activity in various organisms and many have proved invaluable as antibacterial or 
anti fungal agents,anticancer drugs,immunosuppressants,herbicides,tools

for research, and the like. Genetically modified microorganisms have been engineered to produce
such compounds in large amounts. Among these, antibiotics are the secondary metabolites considered among the most important to human therapeutics, and the most extensive use of screens is in the search for compounds with selective toxicity for bacteria, fungi, or protozoa. It is estimated that natural microbial antibiotics provide the starting point for over 75% of
marketed antimicrobial agents.

AVERMECTINS:
Many microorganisms indigenous to the soil, especially actinomycete bacteria and many fungi, produce biologically active secondary metabolites.
Intensive screening of culture supernatants (usually called “fermentation
broths”), rich in secondary metabolites, has led to the discovery of numerous clinically valuable antibiotics, with penicillin as the most famous example, but of many other types of valuable compounds as well. The structures of newly characterized compounds with herbicidal, insecticidal, and nematocidal activities from soil microorganisms are described in the scientific literature at a rate of several hundred each year.
The avermectins were discovered in the early 1980s as a result of a
deliberate search for antihelminthic compounds produced by soil microorganisms. Helminths are parasitic worms that infect the intestines of any
animal unfortunate enough to ingest their eggs. There were two particularly notable features of the screening program. First, the microbial fermentation broths were tested by being administered in the diet to mice infested with the nematode Nematospiroides dubius. Nematodes are a subclass of helminths that includes roundworms or thread worms. Although such an in vivo assay was expensive, it simultaneously tested for efficacy of
the preparation against the nematode and toxicity to the host. Second, to
increase the chance of discovering new types of compounds, the selection of
microorganisms for testing was biased toward those with unusual morphological traits and nutritional requirements. The morphological characteristics of Streptomyces avermitilis, the producer of avermectins, were unlike those of other known Streptomyces species. S. avermitilis produces a family of closely related macrocyclic lactones, compounds that are  active against certain nematodes and arthropods at extremely low doses,but have relatively low toxicity to mammals. These avermectins and their derivatives, as the compounds came to be called, are highly effective in veterinary use  and in treating infestations in humans.
 Avermectins act on invertebrates by activating glutamate-gated chloride channels in their nerves and muscles, disrupting pharyngeal function and locomotion. The paralyzed parasite most likely starves to death. Their selective toxicity- they do not harm  vertebrates – has led
to the conclusion that avermectins affect a specific cellular target either absent or inaccessible in the resistant organisms. The avermectins do not migrate in soils from the site of application and are  subject to both rapid photo degradation and microbial decomposition. Consequently,
avermectins are not expected to persist for a long time in the feces of treated animals. The biological activity and selective toxicity of the avermectins could not have been anticipated even if the structures of these compounds had been known.
The structure of a naturally occurring small molecule with desirable
biological activity is generally used as the starting point for the design and
preparation of semi-synthetic derivatives with improved activity, selectivity,
and stability characteristics. This has proved to be the case for avermectins.
Ivermectin (IVM; 22,23-dihydroavermectin B1), a semisynthetic
derivative of avermectin B1a, is an indispensable drug in mass treatment
programs to eradicate two widespread serious diseases that affect millions
of people and that are caused by nematodes:river blindness (onchocerciasis) and lymphatic filariasis.

River Blindness (Onchocerciasis) and Lymphatic Filariasis
Onchocerciasis, first described in 1875, is caused by a filarial nematode (Onchocerca
volvulus), a parasite transmitted by the bite of infected blackflies of the genus
Simulium. Onchocerciasis is a leading cause of eye disease in Africa, the Eastern
Mediterranean area, and Latin America. In 2002, it was estimated that 17.7 million
people were infected; of these, about 250,000 went blind and another 250,000
suffered significant visual impairment. Ivermectin kills the infectious larvae ofO.
volvulusbut not the adult worms. The disease is controlled by an annual dose of
IVMof150 µg/kg.
Lymphatic filariasis is caused by the nematodes Wuchereria bancrofti, Brugia
malayi,andBrugia timori. The disease is endemic in most of the warm, humid
regions of the world, including South America, Africa, Asia, and the Pacific Islands.
The principal vectors are mosquitoes. Infections may lead to a wide variety of
symptoms, including acute recurrent fever, lymphadenitis, and blood disorders.
IVM controls lymphatic filariasis in a manner similar to that described for onchocerciasis.
Unexpectedly, endosymbiotic bacteria make the decisive contribution to the
onset of river blindness. Bacteria of the genusWolbachiaare essential endosymbionts in all the pathogenic nematodes mentioned above. In humans infected with
O. volvulus, adult worms survive for up to 14 years in subcutaneous nodules and
release millions of microfilariae over this time. The microfilariae migrate through
the skin and enter the eye. When some of these filariae die, the host response may
result in eye inflammation that causes progressive loss of vision and ultimately
leads to blindness. The host immune response plays a critical role in the inflammatory response associated with the pathogenesis of river blindness. This response is
initiated by the release from the dead and degenerating worms of endotoxin-like
molecules originating in theWolbachiaendosymbionts. Consequently, elimination
ofWolbachiaby antibiotic treatment may prevent onchocerciasis.

Sources: Benenson, A. S. (ed.) (1990).Control of Communicable Diseases in Man, 15th Edition
Washington, D.C.: American Public Health Association; Cooper, P. J., and Nutman, T. B. (2002).
Onchocerciasis.Current Treatment Options in Infectious Diseases, 4, 327–335; Brown, R. K., Ricci, F. M., and Ottesen, E. A. (2000). Ivermectin: effectiveness in lymphatic filariasis.Parasitology,121 121, S133–S146; Saint Andr´ e, A., et al. (2002). The role of endosymbioticWolbachiabacteria  in the pathogenesis of river blindness. Science, 295, 1892–1895.

CITED BY Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Lecturer in Pokhara University, Pokhara Bigyan Thata Prabidhi Campus, Prithivi Naryan Campus, Nobel Academy, LA.
Pokhara, Nepal.















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