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ScienceWeek
MICROBIOLOGY: DRUG RESISTANCE AND SOIL MICROBES
The following points are made by Alexander Tomasz (Science 2006 311:342):
1) Following the serendipitous discovery of penicillin in 1928 and streptomycin in 1943, the pharmaceutical industry has been screening thousands of soil samples for antimicrobial agents produced by inhabitant microbes. Chloramphenicol, clavulanic acid, erythromycin, gentamicin, rifampin, teichoplanin, tetracycline, and vancomycin represent only a few products of this spectacularly successful effort, and addition of these agents to the therapeutic arsenal has played a major role in controlling bacterial disease, the primary cause of human mortality in the preantibiotic era.
2) New work[1] provides a view of the flip side of this story. The authors isolated 480 morphologically diverse spore-forming microbes from the soil and tested these not as producers of antimicrobial agents but rather as microbes that are resistant to existing antibiotics. They found that every isolate was resistant to at least six to eight different antimicrobial agents and some to as many as 20. The antibiotics tested included both well-established and recently developed agents, natural products, semisynthetic derivatives, and fully synthetic antimicrobial agents.
3) With multidrug-resistant bacterial pathogens spreading globally and the enormous efforts to trace the source and mechanism of spread of drug-resistant genes and clones [2], the study by D'Costa et al[1]. has particular poignancy. It illuminates the dark side of the antibiotic paradigm: Microbes that synthesize the sophisticated chemicals that have been key to humankind's success in controlling bacterial disease also possess equally sophisticated mechanisms to protect themselves against their own toxic products. Lifted out of this context, these self-protecting mechanisms represent formidable weaponry that could annul the successes of antimicrobial therapy if they were to find their way into human pathogens.
4) The microbes isolated and characterized by D'Costa et al. all belong to the genus Streptomyces, well known for producing multiple antimicrobial agents [3] that suppress the growth and/or kill other susceptible bacterial species in their vicinity. The 480 independent soil isolates examined presumably include producers of antimicrobial agents that also possess matching resistance mechanisms to protect against suicide in this chemical warfare [4,5].
References (abridged):
1. V. M. D'Costa, K. M. McGrann, D. W. Hughes, G. D. Wright, Science 311, 374 (2006)
2. M. Aires de Sousa, H. de Lencastre, FEMS Immunol. Med. Microbiol. 40, 101 (2005)
3. A. Demain, A. Fang, Adv. Biochem. Eng. Biotechnol. 69, 1 (2000)
4. J. Berdy, J. Antibiot. 58, 1 (2005)
5. L. M. Weigel et al., Science 302, [1569] (2003)
Science http://www.sciencemag.org
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MEDICAL BIOLOGY: ON MICROBIAL ANTIBIOTIC RESISTANCE
The following points are made by Martin Leeb (Nature 2004 431:892):
1) In the late 1960s, the battle against bacterial infections was considered won, in the developed world at least. By the time of Woodstock, antibiotics were curing previously lethal infections in a matter of days. Infected cuts and food poisoning were no longer life-threatening, diseases such as syphilis and gonorrhoea seemed to be on the way to eradication, and ancient scourges such as plague and cholera could now be controlled.
2) Now antimicrobial resistance threatens to turn back the clock. Resistance is spreading rapidly, particularly in hospitals, where many different bacterial strains can come into contact with each other and where antibiotics are heavily used. The more an antibiotic is used, the more resistance to it spreads, forcing physicians to try other antibiotics. Even drugs that once served as a last resort are losing their potency. Some believe that the cycle of resistance is inevitable, and that with every new drug we use, we select for resistant microbes that survive and multiply unhampered by treatment with the same antibiotic.
3) The only apparent solution is to continue to develop new drugs. But just as we need them most, the antimicrobial drug pipeline is running dry. Until ten years ago, all major drug companies ran antibacterial research programs. Today, these programs have been drastically pruned, and many have been cut altogether as pharmaceutical companies pursue more lucrative areas, such as chronic illnesses and mood disorders. The desperate nature of the situation led the Infectious Diseases Society of America (IDSA) to issue a white paper in July 2004 calling for a variety of measures to get antibiotic research back on track, starting in the US. The report followed a year-long investigation into the economics of drug development. In the absence of independent action by the pharmaceutical industry, the report says, the US Congress and federal regulatory agencies must step in with financial incentives for pharmaceutical companies to get back into the antimicrobial business.
4) This all makes for a potential healthcare calamity. Although the number of hospital-acquired infections has been gradually declining in the US, a greater proportion of these infections --now about 70% -- are resistant to at least one antibiotic. This results in a delay in effective treatment, prolonging illness and increasing the risk of death. Two million people will pick up an infection in a US hospital this year, for example, and 90,000 of them will die of it, according to estimates by the US Centers for Disease Control and Prevention.(1-3)
References:
1. Wegener, H. C. Curr. Opin. Microbiol. 6, 439-445 (2003)
2. DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. J. Health Econ. 22, 151-185 (2003)
3. Spellberg, B., Powers, J. H., Brass, E. P., Miller, L. G. & Edwards, J. E. Jr Clin. Infect. Dis. 38, 1279-1286 (2004)
Nature http://www.nature.com/nature
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MEDICAL BIOLOGY: ON BACTERIAL ANTIBIOTIC RESISTANCE
The following points are made by Carlos F. Amabile-Cuevas (American Scientist 2003 91:138):
1) Antibiotics are compounds that kill or at least inhibit the growth of bacterial cells without harming the patient. No single antibiotic can kill or inhibit all bacteria. Natural penicillin and macrolides such as erythromycin, for instance, cannot penetrate into the gut bacterium Escherichia coli and its relatives; only a handful of drugs work against the almost impermeable Mycobacterium tuberculosis, which causes tuberculosis. The intrinsic resistance of bacteria defines the "spectrum" of each antibiotic; wide-spectrum antibiotics are effective against a variety of germs, whereas narrow-spectrum antibiotics only control a few species. But the antibiotic resistance we normally speak about refers to cases in which organisms that were originally killed by a certain drug suddenly keep growing in its presence. When a concentration of antibiotic safely attainable in the blood and tissues of a patient no longer affects an organism, we say the strain has become resistant.
2) The first explanation for resistance was that mutations, small changes in the genetic information, of a bacterial cell somehow prevented an antibiotic from acting on it. Certainly, many resistant organisms arose through the acquisition of spontaneous mutations; this is particularly true for germs causing tuberculosis. But, unexpectedly, genes conferring resistance rapidly emerged and accumulated, quickly yielding multi-resistant bacteria -- i.e., strains resistant to three or more antibiotics. Also, some bacteria were found to have the same resistance genes as those found in species that naturally produce antibiotics. (Most antibiotics are obtained from various species of soil bacteria, which have been producing these compounds for millions of years.)
3) It became clear that bacteria can exchange genes, a process known as "horizontal gene transfer". In this way, a mutation conferring antibiotic resistance can be acquired by neighboring bacteria, even if they are very distantly related species. The resistance genes can spread from mutants or even directly from antibiotic-producing species. Furthermore, such genes can accumulate in a single cell, resulting in multi-resistant germs.
4) Bacteria often carry the resistance genes in small DNA molecules called "plasmids", which act as genetic "supplements" to the core genome. Exchanging these supplements is easier than mobilizing genes in the genome. Genes conferring other dangerous traits, such as virulence, are also often found in plasmids.
American Scientist http://www.americanscientist.org
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Notes by ScienceWeek:
Biologists recognize two types of gene transfer from one organism to another: vertical and horizontal. Vertical gene transfer occurs between parents and offspring, and horizontal gene transfer is the transfer that may occur between organisms otherwise.
It is in bacteria that horizontal gene transfer has been studied most extensively, particularly in the last decade. Three types of horizontal gene transfer are known: conjugation, transduction, and transformation.
Conjugation is a type of sexual reproduction exhibited by some bacteria, the process involving the exchange of genetic material by means of a tube or bridge, the transfer of DNA occurring either in one direction or in both directions.
Transduction involves the transfer of genetic material from one bacterium to another with the intermediation of a virus. Essentially, when the virus infects one bacterium, it often carries away pieces of that bacterium's genome, and those pieces, upon the infection of a new bacterium, become incorporated into the second bacterial genome.
Finally, transformation is the process involving the uptake or incorporation of DNA fragments (plasmids) by a bacterium, first observed in 1944 by Oswald Avery.
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