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Antibiotics - their history and future

These are a few notes written to accompany a talk I recently gave.

The history of antibiotics

Inorganic arsenic arsenic compounds have probably been used since prehistory: coloured arsenic oxides may have been used in cosmetics, leading to the serendipitous discovery of their ability to treat skin complaints. Atoxy was so named because it was about many times (perhaps as much as 40 times) less toxic than inorganic arsenic compounds. Initially, its structure was misassigned as a anilide, rather than as an amino arsenic acid, an error rectified by Ehrlich (or his collaborator Bertheim). The first structure proposed for Salversan was also in error: more recent evidence suggests that it does not contain a double As=As bond, and is instead a mixture of a trimer and pentamer.

A 2005 article in chemotherapy provides a good 9-page introduction to the history of Salvarsan 1.

Biological role of antibiotics

Given that man uses some natural antibiotics to treat disease by killing bacteria, it is tempting to fall into a post-hoc ergo propter hoc fallacy, and conclude that this must be the reason why they are produced by microorganisms. But the doses at which many of these compounds have an antibiotic effect is far higher than the concentrations at which they are secreted, and it now appears that many fulfill other roles, such as signaling/quorum-sensing/bio-film formation2.

Antibiotic resistance

Antibiotic resistant bacteria are now a major problem: the most notable diseases that it causes are Methicillin-Resistant Staphylococcus aureus (MRSA), Clostridium difficile, and multi-drug resistant Tuberculosis (TB).

It can arise via a variety of mechanisms including enzymatic degradation of antibiotics, efflux mechanisms that remove antibiotics from the cell, decreased cell wall/membrane permeability to antibiotics, and changes to the target of the antibiotic. A 2008 paper in Science found numerous strains of soil bacteria that were not only resistant to many antibiotics, but were able to subsist on them as their sole carbon source. Worryingly, many of these bacteria are closely related to human pathogens3.

Anti-virulence therapies

Nature Reviews Microbiology published a good review of the potential for treatments that make bacteria less virulent without killing them (antivirulence therapies) in 20084. Virstatin’s effects on production of Cholora Toxin by Vibrio Cholerae were first reported in 20055. It was identified by genetically modifying the O395 strain of Vibrio Cholerae so that the tetracycline resistance gene tetA was places under the same promotor (ctx) as the Cholera Toxin. Thus, whenever cholera toxin was being produced, so was the tetracycline resistance protein. So the bacteria were ordinarily resistant to the antibiotic tetracycline, but if a drug stopped the production of the Cholera Toxin, it would make the bacterium susceptible to the antibiotic. The scientists screened 50,000 compounds by adding them to bacteria along with tetracycline: if the bacteria died, they concluded that the compound might prevent toxin production. Further experiments confirmed that Virstatin did indeed inhibit toxin production without killing the bacteria, and was an effective treatment for cholera in mice. Subsequent work by the same investigators suggests that it may act by preventing dimerization of the transcriptional activator ToxT6.

Phage Therapy

In the former USSR (especially Georgia), bacteriophages—viruses that infect and kill bacteria—are an established treatment for bacterial infections. However, they have both practical and regulatory problems that limit there use in the rest of the world: they act with extreme specificity, requiring the stockpiling of large numbers of different strains, and the careful determination of which bacteria are responsible for an infection; and they are biologic agents (which are harder to characterize than small-molecules), and undergo unpredictable changes due to mutation. Some also have short half-lives in the body, though this can be improved by serial selection

  1. Riethmiller. From Atoxyl to Salvarsan: searching for the magic bullet Chemotherapy (2005) vol. 51 (5) pp. 234-42. doi:10.1159/000087453 

  2. Mlot. Antibiotics in Nature: Beyond Biological Warfare. Science (2009) vol. 324 (5935) pp. 1637 doi:10.1126/science.324_1637 

  3. Dantas et al. Bacteria subsisting on antibiotics. Science (2008) vol. 320 (5872) pp. 100-3 doi:10.1126/science.1155157 

  4. Cegelski et al. The biology and future prospects of antivirulence therapies. Nature reviews Microbiology (2008) vol. 6 (1) pp. 17 doi:10.1038/nrmicro1818 (There is an open-access manuscript of this paper available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211378/</a>) 

  5. Hung et al. Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Science (2005) vol. 310 (5748) pp. 670 doi:10.1126/science.1116739 

  6. Shakhnovich et al. Virstatin inhibits dimerization of the transcriptional activator ToxT. Proceedings of the National Academy of Sciences of the United States of America (2007) vol. 104 (7) pp. 2372-7 doi:10.1073/pnas.0611643104  

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