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Bacterial Resistance to Antibiotics
©2000 Kenneth Todar, University of Wisconsin-Madison
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 never fully developed resistance to penicillin and it remains a reasonable choice antibiotic 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 basis of bacterial resistance to antibiotics
Inherent (Natural) Resistance Bacteria may be inherently resistant to an antibiotic. For example, a streptomycete has some 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).
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 that once designated it 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 of antibiotic chemotherapy.
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