If you have not listened to the @CuriousClinPod most recent podcast (Episode 10: Why does metronidazole treat both bacterial and parasitic infections?) then I suggest you tune in.
curiousclinicians.com/2020/09/30/why…
I'll summarize their show notes here in short #medtweetorial
First a question:
Was metronidazole first used as an antibiotic or as an antiparasitic?
If you guessed antiparasitic, then you would be correct!
It was developed in the 1950s to treat the parasite trichomonas & then was used in the 1960s to treat other parasitic infections, like giardia and amoebiasis.
Only in the 1970s was it noted to be active against Bacteroides fragilis.
It then became widely used as an antibiotic to treat anaerobic bacterial infections.
trimethoprim-sulfamethoxazole is another example
Why does it treat both bacteria and parasites?
Pyruvate metabolism is key.
One must understand the different ways that aerobes and anaerobes metabolize pyruvate.
Aerobes (e.g. Homo sapiens or aerobic bacteria) use the pyruvate dehydrogenase complex to convert pyruvate to acetyl-CoA.
Acetyl-CoA then goes into the Krebs Cycle & ultimately generates ATP.
Anaerobic bacteria & parasites have a completely different mech for processing pyruvate.
They still convert pyruvate to acetyl-CoA but they use a different enzyme called pyruvate:ferredoxin oxidoreductase
This pyruvate:ferredoxin oxidoreductase (PFOR) then catalyzes a red-ox reaction that moves electrons around.
Metronidazole acts as a target for PFOR and gets reduced, effectively activating the drug.
It then accumulates electrons, forms superoxide anions, damages DNA,& kills
In effect, PFOR converts metronidazole into a DNA-damaging toxin, but only does so in anaerobes that utilize PFOR.
This leaves aerobic cells utilizing PDC (e.g., human cells) unaffected.
What else? Glad you asked.
Metronidazole was also used as a radiosensitizer for radiotherapy in cancer therapy.
Experiments done in the 1970s showed that treating hypoxic or anoxic human cells with metronidazole makes them more sensitive to radiation
The mechanism isn’t entirely clear but it may be that the metabolic changes in anoxic cells allowed it to undergo a red-ox reaction necessary to activate it, even w/o PFOR present
More recent studies showed mixed results & it is no longer used but a cool historical association
What did we learn?
1. Although we think of metronidazole mainly as an antibiotic, it actually was developed in the 1950s and 1960s to treat parasites such as trichomonas and amoebiasis.
2. Metronidazole is selectively active against anaerobic bacteria and parasites due to activation by pyruvate:ferredoxin oxidoreductase (PFOR), an enzyme unique to anaerobic organisms.
There is a bonus on the disulfiram-like reaction. Listen to find out. chtbl.com/track/7G6A8F/t…
Awesome episode @tony_breu @HannahRAbrams @AvrahamCooperMD
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