Trust your gut . . . scientifically speaking. From belly-button bacteria to classification of signature microflora (all the various microbes that populate the intestinal tract), it feels like recent popular “culture” grows best in a petri dish. Many scientists now classify humans as superorganisms, meaning our survival depends on a host of “good” internal bacteria that digest fiber, make vitamins, and help the immune system. But what happens when these good bacteria suddenly get wiped out by a non-selective antibiotic? This sets the stage for a Clostridium difficile intestinal conquest.
Simple contact transmits this bacterium between patients in hospitals, causing antibiotic-assisted diarrhea, bloating, and potential colitis. When a patient is treated with a broad-spectrum antibiotic, C. difficile survive by forming spores with tough outer coats, only to thrive again when there are few other bugs in the gut with which to compete.
Two new players have recently entered the fight against the difficult C. difficile: first, Optimer Pharmaceuticals’ new narrow-spectrum antibiotic for C. diff. treatment, Dificid (fidaxomicin), approved in May 2011. This antibiotic macrolide belongs to the tiacumicin class of natural products, members of which have been known since Abbott first isolated compounds from fermentation broths in 1987. Dificid specifically inhibits Clostridium RNA polymerase enzymes; without these enzymes, gene transcription halts, and the cells die.
Clearing the infection is great, but wouldn’t it be nice to ease the intestinal pain while the drug takes hold?
Researchers at UTMB-Galveston might have found a good target for drugs that could do just that. In the August advanced online publications at Nature Medicine, Tor C. Savidge at UTMB-Galveston reports on human metabolites that can inhibit C. difficile toxins TcdA and TcdB, the major agents behind painful antibiotic-assisted diarrhea. S-nitroso-glutathione, a nitroso (NO)-conjugated version of glutathione found in stool samples of infected patients, can “pass off” its NO group to the sulfur of a specific cystine amino acid residue in the toxins, shutting down their activity. The authors point out that instead of active site binding, the normal mode of action for most enzyme inhibitors, this NO seems to inhibit the toxins via an allosteric site, meaning they bind somewhere else on the toxin but still impair its function. Potency for in vitro inhibition is still in the high micromolar range (43-57 µm), but the study may point the way to the development of more selective NO-transfer drugs.
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