Unique bactericidal action of metronidazole

Q: Unlike any other antibiotic, despite extensive global use over decades, resistance to metronidazole is almost unknown. What could be the explanation?

Answer: It seems like a miracle that, unlike any other antibiotic, despite extensive global use over decades, resistance to metronidazole is not known. The explanation lies in its mechanism of action (MOA). Metronidazole kills bacteria, particularly anaerobes, by producing free radicals inside the microbe cytoplasm. So far, microbes have failed to counter this action. This also explains the 'drug concentration proportional bactericidal effect' of metronidazole.

Metronidazole is a low molecular weight compound that easily diffuses across the microorganisms' cell membranes. Inside the microbe, metronidazole is reduced by the pyruvate:ferredoxin oxidoreductase (a system in obligate anaerobes). The reduction of metronidazole creates a concentration gradient that drives the uptake of more drugs and promotes the formation of intermediate compounds and free radicals that are toxic to the cell. It causes DNA strand breakage and fatal destabilization of the DNA helix. This process leads to the toxic-intermediate particles and inactive end products.

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References:

1. Edwards DI. Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action. J Antimicrob Chemother 1993; 31:9.

2. Edwards DI. Reduction of nitroimidazoles in vitro and DNA damage. Biochem Pharmacol 1986; 35:53.

3. Ralph ED, Kirby WM. Unique bactericidal action of metronidazole against Bacteroides fragilis and Clostridium perfringens. Antimicrob Agents Chemother 1975; 8:409.