Antifungal antibiotics

Antifungal antibiotics

Nystatin is an antifungal agent useful in the therapy of nonsystematic fungal infections. It is produced during fermentation by a strain of Streptomyces noursei. This antibiotic was discovered in 1950 by Elizabeth Hazen and Rachael Brown.

Nystatin

The antimicrobial activity of nystatin is restricted to yeasts and other fungi,e.g., Candida, Aspergillus, penicillin, and Botrytis; it is fungicidal in action chemically, nyastatin is a polyene with an empirical formula of C₄₆H₇₅NO₁₈.

Griseofulvin

Griseofulvin is obtained from Penicillin griseofulvin. It is used in the treatment of many superficial fungus infections of the skin and body surfaces and is also effective in the treatment of some systematic (deep-seated) mycoses. The drug is administered orally.

Antiviral chemotherapeutic agents

Antibiotics such as those that we have discussed are generally not effective against viruses. You will recall that viruses are intracellular, and hence the chemotherapeutic agent, in order to attack the virus, must enter the host cells. Also the great must not be toxic to the host cell while exerting an inhibiting action on the virus. This demands a high level of selective toxicity. In cases of infection by bacteria, fungi, or protozoa the infectious agent is acted upon outside the host cells. Additionally, there are many more metabolic processes that can be interrupted with these microorganisms.

Among the more promising of the chemotherapeutic agents for treating viral disease is interferon. Interferon is small glycoprotein substances of which two types are leukocytic interferon and fibroblast interferon. Cells exposed to interferon develop antiviral properties. The antiviral action of interferon is attributed to interference of protein synthesis.

Natural interferons are in very short supply and are expensive. Recent advances in recombinant DNA techniques (genetically engineered bacteria like Escherichia coli to produce interferon on a large scale commercially) have increased the availability of interferon for both chemotherapeutic and experimental use.

Acycloguanosine is a nucleoside analog which is active against the herpes virus in animals. Its mode of action appears to be that of inhibition of nucleotide utilization. A synthetic nucleotide analog, 5’-iododeoxyuridine has been shown to have antiviral activity and promise as an antiviral chemotherapeutic agent. Its mode of action is most likely that of inhibition of nucleic acid synthesis-preventing the incorporation of thymidine into DNA.

Amantadine us a low-molecular weight compound which is very effective against influenza A virus; it is not effective against influenza B. the incidence of influenza A infections is greatly reduced by use of this drug. The mode of action of amantadine is that of interfering with the uncoating of virus particles and the subsequent release of their nucleic acids.

Antitumor antibiotics

Some antibiotics have been found to possess antitumor activity. The anthramycin group (anthramycin, Sibromycin, Tomaymycin, and neothramycin) is an example of potent antitumor agents. Out of the complicating factors associated with the potential use of these anticancer agents is that they are also cardiotoxic, a fact that illustrates the need for a high level of specificity in a chemotherapeutic agent. The antitumor action of these antibiotics is directed toward DNA structure and function. One of the problems is that of determining whether, through the manipulation of the structure of an antibiotic, e.g., anthramycin, one cut the cardiotoxic property without destroying the antitumor property.

Synthetic chemotherapeutic agents

The nitrofurans are antimicrobial drugs which differ from the antibiotics in that they do not occur naturally. The prototype of the nitrogen derivatives is furfural, which can be prepared from corncobs and cornstalks, oat hulls, beet pulp, peanut hulls, and another vegetable by-products. Furfural, an aldehyde derivative of furan chemically known as 2-furaldehyde, was identified in 1832 as an accidental finding during sugar-distillation studies.

However, it was not until 1944 that the American investigators Dodd and Stillman reported on the discovery of the antimicrobial properties of nitrate furan derivatives. They found that a surprisingly high antibacterial effect was conferred upon furans by the addition of a nitro group in the 5-position of the furan ring. Variations in the side chain in the 2-position of 5-nitrofuran provide a wide system spectrum of compounds in this group. Over 1,000 compounds have been synthesized and studied.

The chemical structures of some chemotherapeutic nitrofurans. As a class, the nitrofurans generally are effective against a broad spectrum of both gram-positive and gram-negative bacteria, several pathogenic protozoa, and some fungi which cause superficial infections in both humans and other animals.

Isonicotinic acid hydrazide (isoniazid)

Isoniazid ha an important, through restricted, application in the therapy of disease. It is an example of competitive inhibition affecting a restricted group of microorganisms, the bacteria. It has proved to be very useful in the control of tuberculosis in humans and is more effective when given alternately with streptomycin. Because it is a structural analog of pyridoxine, or vitamin B₆ and nicotinamide, isoniazid can block pyridoxine-and nicotinamide-catalyzed reactions. This may account for its antimicrobial activity.

Nalidixic acid

Nalidixic acid is a synthetic chemical with a structural formula. It is a useful chemotherapeutic agent for urinary-tract infections caused by gram-negative bacteria. Its antimicrobial activity is attributed, at least in part, to inhibition of DNA synthesis.

Development of resistance to antibiotics

Drug resistance is one of the nature’s never-ending processes whereby organisms develop a tolerance for new environmental conditions. Drug resistance may be due to a preexisting factor in the microorganism, or it may be due to some acquired factor. Penicillin resistance, for example, may result from the production of penicilloic acid. On the other hand, some normally susceptible strains of bacteria may acquire resistance to penicillin. Acquired resistance is also due to penicillinase production in genetically adapted varieties of microorganism. In cultures of penicillin-sensitive bacteria, perhaps one organism in a husband million may be a penicillin-resistant mutant. Normally the ratio of sensitive to resistant organisms is maintained, and no problem develops. When penicillin is present, the sensitive strains do not reproduce whereas the resistant mutants do and eventually dominate the population. This has important clinical implications and is one of the practical reasons why research effort has been made to develop synthetic penicillins which are resistant to the action of penicillinase.

Many organisms which do not produce penicillinase are also resistant to penicillin. This suggests an alternative metabolic pathway or enzyme reaction not susceptible to inhibition by penicillin.

Other mechanisms of drug or antibiotic resistance may be due to (1) competitive inhibition between an essential metabolite and a metabolic analog (drug), (2) development of an alternate metabolic pathway which by passes some reaction that would normally be inhibited by the drug, (3) production of an enzyme altered in such a way that it functions on behalf of the cell but is not affected by the drug, (4) synthesis of excess enzyme over the amount that can be inactivated by the antibiotic or drug, (5) inability of the drug to penetrate the cell due to some alteration of the cell membrane, (6) alternation of ribosomal protein structure.

References

Arvind, Keshari K. and Kamal K Adhikari. A Textbook of Biology. Vidyarthi Pustak Bhander.

Michael J.Pleczar JR, Chan E.C.S. and Noel R. Krieg. Microbiology. Tata Mc GrawHill, 1993.

Powar. and Daginawala. General Microbiology.

Rangaswami and Bagyaraj D.J. Agricultural Microbiology.