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Tag words: antibiotic, antimicrobial, antimicrobial agent, antibiotic resistance, penicillin, methicillin, vancomycin.









Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interest include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Antimicrobial Agents in the Treatment of Infectious Disease
(page 1)


(This chapter has 6 pages)

© Kenneth Todar, PhD

Introduction

Most microbiologists distinguish two groups of antimicrobial agents used in the treatment of infectious disease: antibiotics, which are natural substances produced by certain groups of microorganisms, and chemotherapeutic agents, which are chemically synthesized. A hybrid substance is a semisynthetic antibiotic, wherein a molecular version produced by the microbe is subsequently modified by the chemist to achieve desired properties. Furthermore, some antimicrobial compounds, originally discovered as products of microorganisms, can be synthesized entirely by chemical means. In the medical and parmaceutical worlds, all these antimicrobial agents used in the treatment of disease are referred to as antibiotics, interpreting the word literally.

The modern era of antimicrobial chemotherapy began in 1929, with Fleming's discovery of the powerful bactericidal substance, penicillin, and Domagk's discovery in 1935 of synthetic chemicals (sulfonamides) with broad antimicrobial activity.

In the early 1940's, spurred partially by the need for antibacterial agents in WW II, penicillin was isolated and purified and injected into experimental animals, where it was found not only to cure infections but also to possess incredibly low toxicity for the animals. This fact ushered into being the age of antibiotic chemotherapy, and an intense search for similar antimicrobial agents of low toxicity to animals that might prove useful in the treatment of infectious disease. The rapid isolation of streptomycin, chloramphenicol and tetracycline soon followed, and by the 1950's, these and several other antibiotics were in clinical usage.

Microorganisms that Produce Antibiotics


The bacterial colonies at 10 o'clock, 2 o'clock and 8 o'clock on this agar plate are producing antibiotics that inhibit encroachment by the mold which is growing out from the center.

Most of the natural antibiotics that are being used in agriculture and medicine are produced by three unrelated groups of microbes, including eucaryotic molds and two types of spore-forming bacteria. However, many culturable, and some non culturable microbes, have been shown to produce various substances that inhibit other organisms that grow in their space. If we consider antibiotics as secondary metabolites of microbes, it narrows the field to the handful of microbes discussed below.

1. Penicillium and Cephalosporium molds produce beta-lactam antibiotics such as penicillin and cephalosporin and their relatives. They also produce the base molecule for development of semisynthetic beta-lactam antibiotics, such as amoxacillin and ampicillin. Beta-lactams are used to treat about one-third of outpatients with bacterial infections.

The natural habitat of molds is soil. And although sex is sometimes involved, they reproduce by spore formation. They are foremost in their abilities to degrade organic matter, and they play their most important role in natures in biodegradation and the carbon cycle. Most of us know that molds will grow on nearly anything that is organic and moist, so they are also responsible for a lot food spoilage as well as decomposition of our structural materials and textiles. "Nothing is forever", with molds around.


Three colonies of a Penicillium mold growing on an agar medium. The green fuzzy appearance is the asexual spores of the fungus.

2. Actinomycetes, mainly Streptomyces species, produce tetracyclines, aminoglycosides (streptomycin and its relatives), macrolides (erythromycin and its relatives), chloramphenicol, ivermectin, rifamycins, and most other clinically-useful antibiotics that are not beta-lactams. Actinomycetes are the mainstay of the antibiotics industry.

Actinomycetes are a group of branched bacteria that reproduce by spore formation. They come from a phylum of Bacteria, Actinobacteria, and they are landed in Order Actinomycetales. Some of the representative family include such diverse bacteria as Actinomyces, Corynebacterium, Nocardia, Propionibacter, Streptomyces, Micromonospora and Frankia. Most actinomycetes are inhabitants of the soil. The characteristic odor of damp soil is due to the production of substances, called geosmins, by these bacteria



Two different actinomycetes were spotted in the center of the agar plate about two centimeters apart. This peculiar pattern of growth was observed after a 10-day incubation period. What could be going on? Courtesy of Jerry Ensign Department of Bacteriology. "Chance favors the prepared mind."


3. Bacillus species, such as B. polymyxa and B. subtilis, produce polypeptide antibiotics (e.g. polymyxin and bacitracin), and B. cereus produces zwittermicin. Bacillus species have the relatively rare ability to form a type of resting cell called an endospore. Bacilli are Gram-positive, rod-shaped, aerobic bacteria that live in the soil. They play an important ecological role in aerobic decomposition, biodegradation and mineral recycling.



A swirl of Bacillus mycoides colonies growth amidst other bacteria and molds from the soil. The swirls are always counterclockwise, at least in the Northern Hemisphere where I have seen it.

These organisms all have in common that they live in soil and they form some sort of a spore or resting structure. It is not known why these microorganisms produce antibiotics, but the answer may be in the obvious - it affords them some nutritional or spatial advantage in their habitat by antagonizing the competition; or it may be in the subtle - it acts as some sort of hormone or signal molecule associated with sporulation or dormancy or germination. Antibiotics are secondary metabolites and they are produced at the same time that the cells begin their sporulation processes.

Antibiotics tend to be rather large, complicated organic molecules and may require as many as 30 separate enzymatic steps to synthesize. The maintenance of a substantial component of the bacterial genome devoted solely to the synthesis of an antibiotic leads one to conclude that the antibiotic is important, if not essential, to the survival of these organisms in their natural habitat.

Most of the microorganisms that produce antibiotics are resistant to the action of their own antibiotic, although the organisms are affected by other antibiotics, and their antibiotic may be effective against closely-related strains. In most cases, how or why bacteria are resistant to their own antibiotics is also unknown, but it may be worth pondering or studying if we are to understand the cellular and molecular basis of drug resistance in pathogens.



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