Stepping back briefly from the antibiotic discussion on growing resistance and the veritable nose dive of new discoveries, I found that there are actually several alternative methods currently in research that are not only promising but may also change the way we look at fighting bacterial infection.

From the beginning, antibiotics were always viewed as more of a golden, magical pill from some fairy tale than anything. “If you take this golden pill, everything will be perfect and you will live happily ever after!” The early warnings of immanent resistance from the premier scientists who discovered them went unheeded, unheard. There would always be another golden pill, another miraculous cure-all, and life would go on forever without worry. Don’t worry! Science would make it all OK. It was a naïve and fragile pedestal we built and one that came crashing down just as expected.

Facing this cliff of impending antibiotic doom, many scientists agreed that what was needed was not the search for another “magical” cure, but a better understanding of the process of virulence itself. And with that understanding, maybe something in the process itself can be found that is vulnerable. This isn’t a cure-all, however. The expectation is that every virulent agent is different and there might be dozens of alternate processes and modes-of-action, if not more. But if we can learn how the processes works, then we might be able to more accurately target the problem, like using a laser to cut a string rather than our typical approach of an antibiotic cruise missile. Because, while most antibiotics still function in destroying the majority of bacterial maladies, they also wreak havoc and destruction on the vital, internal microbiota that we generally take for granted until it’s gone. It’s the equivalent of bombing Paris to kill the rats.

Several years ago, Lynette Cegelski and a small group from Washington University of St. Louis published a comprehensive review of some of those alternative therapeutic fields; including Quorum sensing, secretion system targeting, and microbial attachment. It is a very good review and well deserving of a read through if you haven’t looked at it already. Yesterday, Ji Yang et al. published a paper in the Journal of Biological Chemistry, which delved into the use of chemical inhibition of the gene expression of the bacteria Citrobacter rodentium. C. rodentium is a mesophilic, gram-negative bacterium which causes severe behavioral changes and diarrhea in mice and is the equivalent of an E. coli infection in humans. Yang targeted the AraC family of regulators which controls the transcription of genes involved in carbon metabolism, stress response and pathogenesis.

Similar to a previous study on ToxT proteins from Vibrio cholerae from Deborah Hung et al. in 2005, Yang screen nearly 12,000 compounds for RegA inhibitors to identify 13 positive compounds. They focused on one compound that completely inhibited the β-gal activity of the test strain, discovered a variant of the chemical which had even more efficacy, and nicknamed it “Regacin”. They reported that regacin actively inhibited C. rodentium’s toxic effects both when administered before inoculation as well as 12 hours after inoculation! Regacin works by interacting directly with the double HTH domain of the molecule, but did not hinder the dimerization of the DNA as did the small molecules from Hung’s research. It also did not have any effect on the rest of the microbiota. Yang further discovered that C. rodentium did not have any effect on the mice when delivered directly to the large intestine. So, by inhibiting its ability to react to conditions in the small intestine, the bacteria is then able to pass harmlessly through the host without becoming virulent. However, the down side is that regacin only seemed to affect some of the RegA targets, such as Rns and RegR, but not others, like AggR or ToxT.

So clearly, this is only the beginning of something promising. But it IS promising, nonetheless.

Yang J, Hocking DM, Cheng C, Dogovski C, Perugini MA, Holien JK, Parker MW, Hartland EL, Tauschek M, Robins-Browne RM. (2013) Disarming bacterial virulence through chemical inhibition of the DNA-binding domain of an AraC-like transcriptional activator. J Biol Chem. Sep 9. [Epub ahead of print].

Cegelski, L., Marshall, G. R., Eldridge, G. R., & Hultgren, S. J. (2008). The biology and future prospects of antivirulence therapies. Nature Reviews Microbiology, 6(1), 17-27.
Hung, D. T., Shakhnovich, E. A., Pierson, E., & Mekalanos, J. J. (2005). Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science, 310(5748), 670-674.

Hung, D. T., Shakhnovich, E. A., Pierson, E., & Mekalanos, J. J. (2005). Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science, 310(5748), 670-674.

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