When the magic bullet goes astray
A close look at metronidazole
Antibiotics are really just poisons that are more poisonous to bacteria than to humans. The idea goes back to Paul Ehrlich, who had the idea of a “magic bullet” that could kill pathogens. The first successful antibiotic was an arsenic compound which was extremely toxic to syphilis bacteria, but only moderately toxic to humans.
Today, we have a panoply of antibiotic classes, each of which exploits a difference between bacterial and human cells. For example, aminoglycoside antibiotics inhibit bacterial ribosomes but not human ones. In this post I want to focus on one class in particular: the 5-nitroimidazole antibiotics, the best known of which is metronidazole.
How does metronidazole work?
Metronidazole is an antibiotic with a pretty cool mechanism of action. On its own, it’s not very toxic. However, if the nitro group is reduced to a nitroso group, the resulting compound is highly reactive and damages a wide variety of cellular molecules, including proteins and DNA.1
As it happens, the insides of bacterial cells are strongly reducing environments,2 which means that metronidazole is a good antibiotic. And because it kills anything with a strongly reducing environment, it’s effective against not only bacteria, but also many eukaryotic parasites like Giardia or Trichomonas vaginalis. Furthermore, it’s hard (though not impossible) for pathogens to evolve resistance, because metronidazole doesn’t target any molecule in particular.
Wait, what else has a reducing environment?
Cancer does! The insides of tumors are usually hypoxic, due to the deranged metabolism of cancer cells. 5-nitroimidazole antibiotics have been tested as cancer chemotherapy drugs, usually in combination with radiation.3 However, toxicity is a big problem, since healthy cells can also be damaged by 5-nitroimidazoles at high doses. And because DNA damage results, 5-nitroimidazoles such as metronidazole are “reasonably anticipated” to be human carcinogens.4
Even at the lower doses used for antibiotic treatment, toxicity to healthy cells can cause side effects. A study of patients treated with metronidazole for infections found that 0.25% of patients suffered neurological side effects requiring hospitalization. Metronidazole can also cause lowered production of white blood cells. As it turns out, hematopoetic stem cells, which give rise to white blood cells, exist in a hypoxic niche in the bone marrow.
Intriguingly, a study in 1999 of metronidazole treatment during hematopoetic stem cell transplants found that it decreased the risk of graft-vs-host disease, which is where the transplanted cells attack the recipient. The authors of that study hypothesized that this was due to effects on intestinal bacteria, but I would offer the alternative hypothesis that the metronidazole is affecting the stem cells directly.
But think of the children!
As a developmental biologist, when I first learned about metronidazole, I thought “that can’t be good for embryos!” Before an embryo implants in the uterus, it has no access to oxygenated blood, so its interior is hypoxic. Notably, many lab protocols for culturing early embryonic cell types (such as naïve pluripotent stem cells) use a low oxygen atmosphere because those cells are adapted to it. Interestingly, in some African countries, women illicitly take high doses of metronidazole for emergency contraception! This is a bad idea for several reasons, but it probably does kill pre-implantation embryos. Effects of metronidazole on later stages of pregnancy are not as bad, because by this point the fetus is no longer as hypoxic. A meta-analysis from 1997 found that metronidazole use during the first trimester of pregnancy was not significantly associated with birth defects (odds ratio 1.08, 95% CI 0.90–1.29).5
However, a more worrisome effect may happen in men. Spermatogonial stem cells (the precursors to sperm) grow in a hypoxic niche within the testes. And pimonidazole, a 5-nitroimidazole antibiotic, is known to be reduced in mouse spermatogonial stem cells, where it reacts with thiol groups on proteins. And if it reacts with proteins, it’s also likely reacting with (and damaging) DNA. Needless to say, DNA damage in sperm precursors is a very bad thing.
Several studies in rodents have indicated that metronidazole harms sperm production. In mice given triple the therapeutic dose, the testes shrank, normal sperm counts decreased, and abnormal sperm counts increased. Likewise, male rats treated with high doses developed infertility, though lower doses did not show this effect. However, as of this writing, there were no studies in Pubmed6 that investigated the effects of metronidazole on human spermatogenesis. I don’t think such a study would be very difficult, since it would only involve collecting and analyzing sperm from metronidazole-treated men and untreated controls. If any andrologists are reading this blog, please consider doing this study!
Conclusions
Metronidazole isn’t so much a “magic bullet” as a “magic cluster bomb”. Sure, it can kill the target, but innocents might be harmed too. It’s best, of course, to not need to take metronidazole at all. So try not to get Giardia! (This is good life advice in general.) Still, the benefits of metronidazole in treating infections are likely worth the side effects. Personally, I would not hesitate to take metronidazole if a doctor prescribed it to me — although I might freeze my sperm first.
The chemistry of metronidazole is a bit more complicated than this simple explanation. For a good review see this paper.
This is also why it’s hard to produce proteins with disulfide bonds in bacteria.
This is because hypoxic cells are more resistant to radiation, so killing them with 5-nitroimidazole drugs provides some synergy.
In case you’re wondering, this is the U.S. government classification, not the IARC (which is much more likely to call things carcinogens without good evidence). The U.S. government has two classifications: compounds which are “Known to be a human carcinogen” (based on strong human data) and ones which are “Reasonably anticipated to be a human carcinogen” (based on strong animal data and/or limited human data).
However, this study was not able to distinguish the effects of metronidazole from the effects of the infections that it was prescribed to treat. Healthy women are not prescribed metronidazole during pregnancy.
Search terms: https://pubmed.ncbi.nlm.nih.gov/?term=(metronidazole)+AND+(spermatogenesis)&filter=hum_ani.humans (or similar)