Antibiotic resistance is becoming a more and more prevalent issue in healthcare, where relatively simple infections can no longer be treated and may end in death. Major healthcare facilities such as hospitals will become central locations of transmission and infection, instead of a place to heal. Based on a report by the CDC Antibiotic Resistance Threats in the United States, 2013, 2 million Americans are infected with resistant organisms each year, 23,000 of which die (CDC, 2013). In economic terms, $20 billion is spent each year on healthcare as a result of resistant bacteria. Based on the timeline of antibiotic resistance identification (figure 1) it is clear that resistance is not just an event of recent times but ongoing through the 20^th century. Thus it is of great importance to understand the mechanisms that induce resistance.

History shows that new incidences of resistance will arise, even with the development of new antibiotics. SOS response is an inducible DNA repair and mutagenesis pathway that is stimulated by DNA damage (Cirz et al., 2005). This pathway is important as it suggests that bacteria play an active role in the mutation of their genome instead of utilizing mutations as they occur by chance (Cirz et al., 2005). Furthermore, the SOS response pathway is found in a wide range of bacteria, which implies the significance of this pathway (Michel, 2005).

The SOS response is induced when DNA damage yields high concentrations of single stranded DNA, which activates the RecA protein (Radman, 2005). The RecA protein then binds to lexA, a repressor protein that utilizes a helix-turn-helix structure as a DNA binding domain (Fogh et al., 1994). The binding of RecA to lexA initiates the autoproteolysis of lexA, and allows Pol II, Pol IV and Pol V to be expressed to repair DNA and induce mutagenesis, as seen in figure 2. One study showed that preventing lexA cleavage in the pathogenic E. coli strain ATCC 25922 resulted in an inability to produce ciprofloxacin resistance (Cirz et al., 2005). The same study then systematically deleted individual and combinations of the 3 lexA-repressed proteins to find that the removal of any polymerase led to unsuccessful resistance development (Cirz et al., 2005)

Based on this study, it is clear that SOS response plays a vital role in the development of antibiotic resistance, and RecA or lexA would be viable drug targets. In conclusion, using RecA or lexA as a drug target would be an effective way of reducing the development of antibiotic resistance in bacterial species. The clinical and economic benefits of this drug would be extraordinary, and prevent current and future antibiotics from becoming obsolete.

 

Works Cited:

CDC, 2013. Antibiotic resistance threats in the United States, 2013.

Cirz, R.T. et al., 2005. Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance. PLoS Biology, [online] 3(6), p.e176. Available at: <http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pbio.0030176> [Accessed 24 Oct. 2013].

Fogh, R.H. et al., 1994. Solution structure of the LexA repressor DNA binding domain determined by 1H NMR spectroscopy. The EMBO journal, [online] 13(17), pp.3936–3944. Available at: <http://www.ncbi.nlm.nih.gov/pubmed/8076591>.

Michel, B., 2005. After 30 years of study, the bacterial SOS response still surprises us. PLoS biology, [online] 3(7), p.e255. Available at: <http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1174825&tool=pmcentrez&rendertype=abstract> [Accessed 22 Aug. 2012].

Radman, M., 2005. Bacterial SOS May Be the Key to Combating Antibiotic Resistance. PLoS Biology, [online] 3(6), p.e221. Available at: <http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pbio.0030221> [Accessed 24 Oct. 2013].