In the survival stakes, man’s race to develop antibiotics to kill our bacterial foes, has instead put the pedal to the metal, accelerating the directed evolution of untreatable, multi-resistant bacterial strains, threatening to send us back to pre-antibiotic days. The action of antibiotics creates selective pressure, which may ultimately induce the error-prone ‘SOS’ DNA repair response in bacteria, creating mutations in the hope that diversity brings survival. The number of mutated strains showing antibiotic resistance is growing at an alarming rate!
The SOS response involves formation of the RecA-DNA protein bridge, in an attempt to repair DNA through homologous recombination. Common to all bacteria, RecA filaments are polymers of ATP bound RecA monomers. Inhibition of the RecA filament polymerization holts not only DNA repair, but also the possibility of mutagenic resistant survivors.
As no natural products are known to inhibit RecA activity, Cline, Holt and Singleton (2007) recently published their proteomically designed peptide, INhibitory PEPtide, INPEP-STP, which specifically and irreversibly binds to the N-terminus of RecA proteins. It prevents ATP hydrolysis and interfacing of RecA monomers to form filaments. INPEP-STP produced a 100% reduction of in vitro RecA activity and provides a potentially potent adjunct to antibiotic therapy.
If we continue applying selective pressure with our current antibiotic regimes, the necessity in simultaneously disrupting the SOS response and therefore accelerated evolution in bacteria with adjunct products, such as INPEP-STP, is clearly demonstrated by the work of Cirz, Romesberg et al (2005).
Otherwise, we are just applying grease to the tracks of bacterial evolution and we risk being mown down in the process.
The SOS response involves formation of the RecA-DNA protein bridge, in an attempt to repair DNA through homologous recombination. Common to all bacteria, RecA filaments are polymers of ATP bound RecA monomers. Inhibition of the RecA filament polymerization holts not only DNA repair, but also the possibility of mutagenic resistant survivors.
As no natural products are known to inhibit RecA activity, Cline, Holt and Singleton (2007) recently published their proteomically designed peptide, INhibitory PEPtide, INPEP-STP, which specifically and irreversibly binds to the N-terminus of RecA proteins. It prevents ATP hydrolysis and interfacing of RecA monomers to form filaments. INPEP-STP produced a 100% reduction of in vitro RecA activity and provides a potentially potent adjunct to antibiotic therapy.
If we continue applying selective pressure with our current antibiotic regimes, the necessity in simultaneously disrupting the SOS response and therefore accelerated evolution in bacteria with adjunct products, such as INPEP-STP, is clearly demonstrated by the work of Cirz, Romesberg et al (2005).
Otherwise, we are just applying grease to the tracks of bacterial evolution and we risk being mown down in the process.
Written by: s41238075
Primary reference:
Cline D., Holt S., Singleton S., 2007, Inhibition of Escherichia coli RecA by rationally redesigned N-terminal helix, Org. Biomol. Chem., 5, 1525-1528
http://www.rsc.org/publishing/journals/OB/article.asp?doi=b703159a
Secondary references:
Cirz R., Chin J., Andes D., de Crecy-Lagard V., Craig W., Romesberg F., 2005, Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance, PLoS Biology, 3;6, pp1024-1033
http://dx.doi.org/10.1371/journal.pbio.0030176
Gene M., 2005, Evolution Under Intrinsic Control,
http://www.idthink.net/biot/lexA/index.html
