David Wheldon Comments on How Flagyl/Tinidazole works on Cpn

There are reasons for thinking that the MBC (Minimum Bacteriocidal Concentration) of metronidazolei against cpni 'frozen' by protein-synthesis inhibitors may be quite low. Metronidazole enters the bacterial cell by passive diffusion. Of itself it has little antibacterial activity, but in susceptible bacteria its highly reactive metabolites break the bacterial DNA at the AT base-pair; these are single-strand breaks, and are repairable. In ordinary anaerobic bacteria the outcome (death or survival) is decided by the equation of breakage versus repair.

Under normal circumstances, the organism, at the first sign of DNA damage, will switch on its 'last chance saloon' repair mechanism. However, this repair mechanism requires the synthesis of at least 15 proteins. The 'frozen' organism is unable to make them. Thus DNA damage is likely to be ongoing and remain unrepaired. New metronidazole is also entering the bacterial cell by passive diffusion all the time, there being a concentration-gradient across the bacterial cell-wall as the intracellulari metronidazole is converted to active metabolite. Further, one might postulate that the endosome is likely to maintain a high concentration of active metabolite: the organism's refuge becomes its death-chamber. If this is the case, one could make an argument for a sustained rather than a high-dose medication. Speaking from my own experience I experienced little during my first five-day pulse of metronidazole (400mg three times a day): the fireworks came on day 4 of the second pulse, and continued long after stopping the drug. And what fireworks they were. I wish I had filmed the muscle fasciculationsi. Metronidazole does not now affect me, apart from its rather nauseating taste.

The metronidazole is active against chlamydia only when protein-synthesis inhibitors have forced the chlamydia to switch to a sluggish anaerobic pathway. The same protein-synthesis inhibitors then prevent repair of DNA damage caused by metronidazole-metabolite. Synergy on two fronts: I have to say it again - it's one of the neatest concepts in antimicrobial therapeutics. My admiration goes to the Vanderbilt workers who first considered this.