Infectious Diseases

Antibiotics and Resistance a Historical Overview



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Bacteria have been becoming resistant to antibiotics since time immemorial. In 1877, the father of modern microbiology, Lois Pasteur, noted that some bacteria secrete compounds that kill other bacteria. These compounds now termed antibiotics are part of Nature's ongoing arms race. Bacteria are in competition with other bacteria, fungi, plants and other organisms for limited resources. If you can kill the competition, then there is more for you. If you can avoid being killed, you can still compete. Antibiotics and resistance to them are a very visible example of evolution in action.

Paul Ehrlich's lab, in the first systematic screen for antibiotics in 1909, discovered compounds that killed syphilis-causing bacteria. The first generally effective antibiotics to be introduced into clinics worldwide, during the late 1930s, were the sulfa drugs; synthetic chemicals that include a sulfonamide group. Prontosil was the first of these, and its introduction revolutionized medicine. In the early 1930s, approximately half of all hospital patients were being treated for a microbial infection. The greatest cause of death amongst Americans aged 15 to 45 during this period was tuberculosis, caused by the bacteria Mycobacteria tuberculosis. Antibiotics were truly magic bullets, and have been estimated to have added 10 years to the life expectancy of Americans. Isoniazid, a sulfa drug developed in 1952, is still a primary drug used in the treatment of tuberculosis.

Penicillin was then introduced during the 1940s, becoming available to the public after World War II, and for the most part eventually replaced the sulfa drugs as penicillin was proven safer and more effective. Penicillin is a natural product, synthesized by (amongst others) fungi of the genus Penicillium. It was discovered in 1929 by Alexander Fleming, and developed by Florey and Chain during the 1930s. Penicillin is the archetypal beta-lactam antibiotic, a class that now comprises penicillins, cephalosporins, carbapenems and monobactams. Together, the beta-lactams (now usually produced synthetically) are some of the most widely prescribed drugs.

The beta-lactams and sulfonamides, as well as streptomycins, tetracyclines, chloramphenicol; erythromycins, neomycins, and polymyxins were all discovered during the so-called golden years of antibiotic research in two decades following the release of Prontosil. Each of these classes represents a group of related structures, and share a common mode of action. All beta-lactams, for example, target cell wall biosynthesis in gram positive bacteria. Very few new classes have been reported since, although certain drugs, such as the cephalosporins, have gone through many "generations" of improvement.

RESISTANCE TO ANTIBIOTICS

The first reports of bacteria developing resistance to antibiotics started to come during the same golden era. Just a few short years after the introduction of penicillin, resistant Staphylococcus aureus were reported in 1947, the first such report of emerging resistance. Methicillin (the actual penicillin used at the time) resistant S. aureus (MRSA) are now, according to the Centers for Disease Control, the most frequently identified antimicrobial drugresistant pathogen in US hospitals. Multiply-resistant S. aureus infections with the organism being resistant to methicillin and other penicillins, tetracycline and erythromycin now account for about 50 % of all S. aureus infections in the US. During the early 1990s, vancomycin (a glycopeptide fast-track approved by the FDA in 1954) was the only antibiotic capable of treating such infections, although vancomycin was never the first choice drug. Vancomycin-resistant S. aureus (VRSA) were reported in hospitals in Europe and the USA in 1996. Linezolid, the first commercially available oxazolidinone was developed in the 1990s and became the last line of defense against MRSA and VRSA. Linezolid-resistance in S. aureus was reported in 2001.

Reports of M. tuberculosis becoming resistant to streptomycin appeared at the end of the 1940s, only a short time after the introduction of that drug. Streptomycin is also interesting as its efficacy against tuberculosis was tested in the first published randomized clinical trial (started in 1947) setting a new standard for how the effectiveness of all future drugs would be tested.

Likewise with other antibiotics: resistance can be tracked to a few years after their introduction. Choramphenicol, introduced clinically in 1949, inhibits protein synthesis in susceptible bacteria. Three known mechanisms of resistance are known: mutation of the target, reduced membrane permeability and plasmid-borne inactivators. The first reports of resistance were being reported in 1950. Rifampicin, a rifamycin introduced around 1960 and widely used to treat tuberculosis. By 1971, 2.5 % of all tuberculsosis isolates were resistant to rifampicin.

WHY RESISTANCE OCCURS

Bacterial resistance to antibiotics is a natural part of how these drugs work. Antibiotics are, usually, small chemicals that bind at the active site of an enzyme and inhibit its activity. Enzymes targeted by antibiotics are generally essential for growth of the bacteria eliminating this activity renders the bacteria unable to divide, produce new protein or DNA, or some other vital facet of life. The bacteria therefore either stop growing, or die.

Within a population of bacteria, variations naturally occur. Not every single bacterium is an exact copy of another. Subtle changes at the DNA level between individuals mutations cause usually subtle differences in the proteins encoded by that piece of DNA. An amino acid change in the antibiotic binding region of a target protein can cause the protein to no longer bind that antibiotic, hence conferring resistance. In a large pool of bacteria, most will be the wild type or normal sequence, and be sensitive to the antibiotic. However, a few will have a mutation that confers resistance. Treatment with the antibiotic will kill of those that are sensitive, leaving those that are resistant.

Resistance to beta-lactam antibiotics occurs through a somewhat different mechanism, although the general concept remains the same. Instead of the target enzyme acquiring resistance, a beta-lactamase and enzyme that destroys penicillins becomes activated, thereby reducing the effective concentration of the drug.

Efflux pumps are another common source of resistance. If the drug can be pumped out of the cell away from the target protein, it can no longer cause inhibition.

A final method of resistance is to change biochemical pathways altogether. Sulfonamide drugs inhibit the synthesis of folic acids and nucleic acids from para-aminobenzoic acid. Some strains develop resistance by bypassing this step, and utilizing preformed folic acid from their environment instead.

BIOCIDES

Biocides, such as bleach, work in a different manner to antibiotics. They destroy the bacteria by chemical or physical means in a non-specific manner that cannot be overcome by mutation. Triclosan a compound put into consumer products as diverse as toothpaste, the handles of toothbrushes, socks and laundry detergent was initially claimed to work as a biocide. However, further study has shown that it in fact targets a specific protein within the cell and causes cell death by inhibition of cell wall biosynthesis, at least in some organisms. As such, resistance to triclosan is likely to emerge sometime in the near future. EU countries have wisely started to voluntarily withdraw triclosan containing products from sale; no such good sense is being displayed in the USA as of yet, however.

CONCLUSIONS

Bacteria will become resistant to our best efforts to develop antibiotics. They have, after all, been playing this game of cat and mouse with fungi for billions of years. They've had a bit of practice. But hope is not lost yet. By judicious use of the drugs we do have only using them when needed and completing the course we are given we can keep going a while longer with what we have. We are learning how bacteria become resistant, and are able to overcome those mechanisms, often by step-wise alterations of the drug, as has been seen in first, second, third and now fourth generation cephalosporins. We are able to use combination therapy: using two or more drugs that target different enzymes. Alternatively, giving one drug (such as thiolactomycin derivatives) that targets two different, key, enzyme activities is also possible in the case of condensing enzyme of bacterial fatty acid synthesis. New diagnostic tools allow for rapid identification of pathogenic strains, allowing physicians to prescribe the best drug possible. With continued research, we can decipher more about the biology of bacteria and the roles the key enzymes play in the pathways they control. New drug scaffolds need to be found also, to inhibit old and new targets. The bacteria have not won yet, but we must remain vigilant unless they do!

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