Friday, December 2, 2011

Active role of the stringent response in antibiotic tolerance

From time to time we try killing bacteria with antibiotics. Most of the bugs die, but not all. These survivors fall into two categories: resistant bugs and tolerant bugs. Resistant bugs have specific mechanisms counteracting the drug: mutations in the target site, enzymes destroying the antibiotic, etc. Tolerant bugs are not getting killed using some more general approach, such as forming a biofilm efficiently shielding them from contact with the drug or shutting down its biosynthetic activity and waiting for the better days to come.

The stringent response is a mechanism rewiring the bacterial physiology under stress. It changes many things simultaneously, and, not surprisingly, functionality of the stringent response is linked to antibiotic tolerance. However, the big question here is the nature of this link: do bugs need functional stringent response in order to tolerate the drug just because relaxed bugs do not shut down their growth when needed and die, or does the stringent response induce production of certain specific enzymes protecting from the drug?

Recent report by Nguyen and colleagues seems to settle this question. Using series of in vivo experiments with E. coli knock-out strains deficient either in stringent response per se (knock-outs of RelA and SpoT) or in down-stream stringent response-regulated targets they show that the main source of antibiotic tolerance is not a general biosynthetic shut-down. Specifically, they identify two genes induced during the stringent response - superoxide dismutase (SOD) and catalase - to be crucial for bacterial survival in the presence of antibacterials.  What these do, they protect the bug from the hydroxyl radical. And build-up the latter was recently identified as a common mechanism causing the cell death during treatment by different unrelated antibacterials


Nguyen at al., Science (2011) 334, pp. 982-986 PIMD 22096200

Kohanski et al. Cell (2007) 130, pp. 797-810 PIMD 17803904

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