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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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Control of Microbial Growth (page 6)

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Bacterial resistance to antibiotics

Penicillin became generally available for treatment of bacterial infections, especially those caused by staphylococci and streptococci, about 1946. Initially, the antibiotic was effective against all sorts of infections caused by these two Gram-positive bacteria. Resistance to penicillin in some strains of staphylococci was recognized almost immediately. (Resistance to penicillin today occurs in as many as 80% of all strains of Staphylococcus aureus). Surprisingly, Streptococcus pyogenes (Group A strep) have not fully developed resistance to penicillin and it remains a reasonable drug of choice for many types of streptococcal infections. Natural penicillins have never been effective against most Gram-negative pathogens (e.g. Salmonella, Shigella, Bordetella pertussis, Yersinia pestis, Pseudomonas) with the notable exception of Neisseria gonorrhoeae. Gram-negative bacteria are inherently resistant because their vulnerable cell wall is protected by an outer membrane that prevents permeation of the penicillin molecule.

The period of the late 1940s and early 1950s saw the discovery and introduction of streptomycin, chloramphenicol, and tetracycline, and the age of antibiotic chemotherapy came into full being. These antibiotics were effective against the full array of bacterial pathogens including Gram-positive and Gram-negative bacteria, intracellular parasites, and the tuberculosis bacillus. However, by 1953, during a Shigella outbreak in Japan, a strain of the dysentery bacillus was isolated which was multiple drug resistant, exhibiting resistance to chloramphenicol, tetracycline, streptomycin, and the sulfanilamides. There was also evidence mounting that bacteria could pass genes for multiple drug resistance between strains and even between species. It was also apparent that Mycobacterium tuberculosis was capable of rapid development of resistance to streptomycin which had become a mainstay in tuberculosis therapy.

By the 1960's it became apparent that some bacterial pathogens were developing resistance to antibiotic-after-antibiotic, at a rate faster than new antibiotics could be brought to market. A more conservative approach to the use of antibiotics has not been fully accepted by the medical and agricultural communities, and the problems of emerging multiple-drug resistant pathogens still loom. The most important pathogens to emerge in multiple drug resistant forms so far have been Mycobacterium tuberculosis and Staphylococcus aureus.
 

The basis of bacterial resistance to antibiotics


An antibiotic sensitivity test performed on an agar plate. The discs are seeded with antibiotics planted on the agar surface. Interpretation of the size of the bacterial "zones of inhibition" relates to the possible use of the antibiotic in a clinical setting. The organism is resistant to the antibiotics planted on the plate at 5 o'clock and 9 o'clock.

Bacterial resistance to an antimicrobial agent may be due to some innate property of the organism or it may due to acquisition of some genetic trait as described below.

Inherent (Natural) Resistance - Bacteria may be inherently resistant to an antibiotic. For example, a streptomycete may have some natural gene that is responsible for resistance to its own antibiotic; or a Gram-negative bacterium has an outer membrane that establishes a permeability barrier against the antibiotic; or an organism lacks a transport system for the antibiotic; or it lacks the target or reaction that is hit by the antibiotic.

Acquired Resistance - Bacteria can develop resistance to antibiotics, e.g. bacterial populations previously-sensitive to antibiotics become resistant. This type of resistance results from changes in the bacterial genome. Acquired resistance is driven by two genetic processes in bacteria: (1) mutation and selection (sometimes referred to as vertical evolution); (2) exchange of genes between strains and species (sometimes called horizontal evolution or horizontal gene transmission).

Vertical evolution is strictly a matter of Darwinian evolution driven by principles of natural selection: a spontaneous mutation in the bacterial chromosome imparts resistance to a member of the bacterial population. In the selective environment of the antibiotic, the wild type (non mutants) are killed and the resistant mutant is allowed to grow and flourish. The mutation rate for most bacterial genes is approximately 10-8. This means that if a bacterial population doubles from 108 cells to 2 x 108 cells, there is likely to be a mutant present for any given gene. Since bacteria grow to reach population densities far in excess of 109 cells, such a mutant could develop from a single generation during 15 minutes of growth.

Horizontal gene transmission (HGT) is the acquisition of genes for resistance from another organism. For example, a streptomycete has a gene for resistance to streptomycin (its own antibiotic), but somehow that gene escapes and gets into E. coli or Shigella. Or, more likely, some bacterium develops genetic resistance through the process of mutation and selection and then donates these genes to some other bacterium through one of several processes for genetic exchange that exist in bacteria.

Bacteria are able to exchange genes in nature by three processes: conjugation, transduction and transformation. Conjugation involves cell-to-cell contact as DNA crosses a sex pilus from donor to recipient. During transduction, a virus transfers the genes between mating bacteria. In transformation, DNA is acquired directly from the environment, having been released from another cell. Genetic recombination can follow the transfer of DNA from one cell to another leading to the emergence of a new genotype (recombinant). It is common for DNA to be transferred as plasmids between mating bacteria. Since bacteria usually develop their genes for drug resistance on plasmids (called resistance factors [R-factors] or resistance transfer factors [RTFs]), these genetic elements play heavily in the of spread drug resistance to other strains and species during genetic exchange processes.

The combined effects of fast growth rates, high populations of cells, genetic processes of mutation and selection, and the ability to exchange genes, account for the extraordinary rates of adaptation and evolution that can be observed in the bacteria. For these reasons bacterial adaptation (resistance) to the antibiotic environment seems to take place very rapidly in evolutionary time: bacteria evolve fast!
 

The medical problem of bacterial drug resistance

Obviously, if a bacterial pathogen is able to develop or acquire resistance to an antibiotic, then that substance becomes useless in the treatment of infectious disease caused by that pathogen (unless the resistance can somehow be overcome with secondary measures). So as pathogens develop resistance, we must find new (different) antibiotics to fill the place of the old ones in treatment regimes. Hence, natural penicillins have become useless against staphylococci and must be replaced by other antibiotics; tetracycline, having been so widely used and misused for decades, has become worthless for many of the infections where it once worked as a "wonder drug".

Not only is there a problem in finding new antibiotics to fight old diseases (because resistant strains of bacteria have emerged), there is a parallel problem to find new antibiotics to fight new diseases. In the past two decades, many "new" bacterial diseases have been discovered (Legionnaire's disease, gastric ulcers, Lyme disease, toxic shock syndrome, "skin-eating" streptococci). We are only now able to examine patterns of susceptibility and resistance to antibiotics among new pathogens that cause these diseases. Broad patterns of resistance exist in these pathogens, and it seems likely that we will soon need new antibiotics to replace the handful that are effective now against these bacteria, especially as resistance begins to emerge among them in the selective environment antibiotic chemotherapy.

Alternatives to Antibiotics

Phage therapy is the therapeutic use of lytic bacteriophages to treat pathogenic bacterial infections. Phage therapy is an alternative to antibiotics being developed for clinical use by research groups in Eastern Europe and the U.S. After having been extensively used and developed mainly in former Soviet Union countries for about 90 years, phage therapies for a variety of bacterial and poly microbial infections are now becoming available on an experimental basis in other countries, including the U.S. The principles of phage therapy have potential applications not only in human medicine, but also in dentistry, veterinary science, food science and agriculture.

An important benefit of phage therapy is derived from the observation that bacteriophages are much more specific than most antibiotics that are in clinical use. Theoretically, phage therapy is harmless to the eucaryotic host undergoing therapy, and it should not affect the beneficial normal flora of the host. Phage therapy also has few, if any, side effects, as opposed to drugs, and does not stress the liver. Since phages are self-replicating in their target bacterial cell, a single, small dose is theoretically efficacious. On the other hand, this specificity may also be disadvantageous because a specific phage will only kill a bacterium if it is a match to the specific subspecies. Thus, phage mixtures may be applied to improve the chances of success, or clinical samples can be taken and an appropriate phage identified and grown.

Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics, particularly in the country of Georgia. They are reported to be especially successful where bacteria have constructed a biofilm composed of a polysaccharide matrix that antibiotics cannot penetrate.




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