The popular press has only recently begun to appreciate the growing threat posed by antibiotic resistant bacteria (1,2). According to the Infectious Disease Society of America over 70% of hospital-acquired infections in the United States are resistant to one or more antibiotics. A single resistant bacterial pathogen, Methicillin-resistant Staphylococcus aureus caused 18,964 mortalities in the United States in 2006 alone (3). This is particularly worrisome, as the repertoire of compounds in our arsenal to tackle this threat has remained stagnant.

When first developed, penicillin was widely hailed as a cure-all. Indeed, the development of penicillin led to a rapid decrease in fatalities caused by bacterial infections. People believed that we had finally defeated the scourge of bacterial diseases. This included experts such as the US Surgeon General who remarked, in a message to the US Congress in 1969, "It is time to close the book on infectious diseases . The war against pestilence is over." However, since then, clinically significant resistance has evolved in response to the deployment of any novel antibiotic in as little as a few years (4). Due to an increase in the mobility of the population, resistant strains that might previously have been restricted to a particular locale can spread very quickly. Furthermore, the looming specter of bio-terrorism would suggest that such resistant strains could easily be exploited by an unscrupulous individual for a targeted attack. Despite this, not enough effort is being devoted to developing new antibiotics. As Steven Projan at Wyeth Research so sapiently observes, if society were to continue on its current course “what is now perceived as the sound of a yapping lap dog nipping at our heels will become the deafening gallop of hooves of the steed carrying Pestilence, one of the four horsemen of the Apocalypse (5).”

Bacteria use a remarkable variety of strategies to resist the toxic effects of antibiotics. They might produce enzymes that inactivate the drug, such as beta lactamases that can degrade ampicillin. Alternatively, bacteria may alter the structure of the target protein to which a drug binds inside the cell. This is one mechanism by which bacteria acquire resistance to vancomycin. In some cases, bacteria might use an alternative metabolic pathway, instead of the one affected by an antibiotic. Bacteria such as the notoriously drug resistant pathogen, P. aeruginosa are also able to actively pump out antibiotics from their cells, to prevent them from accumulating at toxic levels. Bacterial populations also contain a small subset of bacteria, known as “persisters” that are intrinsically tolerant to antibiotics, although why this is the case is not very well understood (6).

Some bacteria within a population might have pre-existing proteins that enable them to degrade drugs (as described above). These bacteria are selected for when the population is treated with antibiotics. Alternatively, bacteria might evolve resistance to antibiotics through mutations. Mutations often arise as a result of selective pressure imposed by antibiotic treatment itself. Bacteria that are not resistant are also able to acquire genes coding for proteins that confer antibiotic resistance from other bacteria, through a mechanism known as horizontal gene transfer. Horizontal gene transfer allows bacteria to have dynamic genomes, in which DNA is frequently added into or removed from the chromosome, unlike higher organisms. Whole-genome sequencing suggests that this horizontal gene transfer is a major contributor to the evolution of antibiotic resistance (7).

Recent research by George Church and colleagues at Harvard Medical School suggests that we have even more reason to be worried (8). They cultured a variety of bacteria from 11 diverse soils. Remarkably, they found that some of these bacteria were not only resistant to antibiotics; but in fact they were able to subsist on antibiotics as a sole carbon source. To put it another way, the bacteria were using the antibiotics for nourishment. They used a representative set of 18 antibiotics consisting of compounds from all major antibiotic classes. Each and every one of these antibiotics could be used by one or more bacterial species as a food source. The bacteria were resistant to 14 out of the 18 antibiotics at concentrations as much as 50 times higher than the typical dose used clinically. They observed that such bacteria are widely spread in the environment and some of them are closely related to pathogenic species of bacteria. Since bacteria exchange genetic information with each other through horizontal gene transfer, these soil bacteria could serve as a reservoir of antibiotic resistance genes that pathogenic bacteria could acquire, further exacerbating the threat of antibiotic resistant bacteria.

In conclusion, I would like to point out that none of the issues raised in this blog post have been exaggerated and I would like to encourage all readers to use antibiotics responsibly.

References

1) “Officials: Not enough drugs for Europe superbugs” Malin Rising, Associated Press Writer, September 17, 2009
2) “Drug-Resistant Staph: What you need to know” Tara Pope, The New York Times, October 23, 2007
3) CDC, Centers for Disease Control and Prevention Active Bacterial Care Surveillance Report, Emerging Infectious Disease Program Network Methicillin Resistant Staphylococcus Aureus, 2006 (CDC, Atlanta, GA, 2006)
4) “Targeting virulence: a new paradigm for antimicrobial therapy” Clatworthy et al., Nature Chemical Biology 3, 541-548 (2007)
5) “Why is Big Pharma getting out of antibacterial drug discovery?” Steven Projan Current Opinion in Microbiology 6, 5, 427-430 (2003)
6) “Persister cells, dormancy and infectious disease” Kim Lewis Nature Reviews Microbiology 5, 48-56 (2007)
7) "Lateral gene transfer and the nature of bacterial innovation" Ochman et al., Nature 405, 299-304 (2000)
8) “Bacteria subsisting on antibiotics” Dantas et al. Science 320, 100 (2008)