Metronidazole (C6H9N3O3) is an antibacterial and antiprotozoal agent that has gained widespread use as a drug. It is classified as a nitroimidazole, and it is a synthetic derivative of azomycin. It is sold in the United States as Flagyl.

History

Metronidazole was first used against parasites such as Trichomonas vaginalis and Entamoeba histolytica. The antibacterial activity of metronidazole was discovered purely by accident in 1962 when a patient was cured of both trichomoniasis and bacterial gingivitis, and since then, the use of metronidazole has skyrocketed. Metronidazole has remained popular because it is inexpensive, has good tissue penetration, and has relatively mild side effects. Metronidazole is also effective against a wide variety of pathogenic critters, such as Trichomonas vaginalis, Entamoeba histolytica, Giardia lamblia, Clostridium difficile, and Helicobacter pylori.1

However, the mechanism by which metronidazole works has until recently been poorly understood, and even today some questions linger. This is probably because, in the past, noone really cared as long as it worked, but as concerns about resistance to metronidazole are beginning to surface in the scientific community, a need for research into the matter has been recognized.*

Trends

Metronidazole-sensitive organisms all live under anaerobic conditions, and the more complex parasites all lack mitochondria, centrioles, and introns. This implies that metronidazole is activated by enzymes specific to anaerobic organisms, and this notion has been upheld by various findings. For instance, researchers have shown that metronidazole acts against Trichomonas vaginalis by binding to a protein called Trichomonas vaginalis ferredoxin (hereafter referred to as TvFd), a protein that is found in the hydrogenosome of the protozoan and is a component of the creature's electron transport pathway.

Mechanism

It was originally thought that metronidazole was a protein inhibitor and disrupted essential metabolic pathways, but experiments have squashed this idea. Research shows that metronidazole is activated when it gains an electron from the molecule that activates it. In the case of Trichomonas vaginalis, that molecule is TvFd.

It has been proven experimentally that upon gaining an electron, metronidazole becomes extremely reactive and destroys cellular DNA. However, the exact mechanism by which metronidazole is reduced has not yet been elucidated.**

Risks, or Possible Causes for Concern
Side Effects

Metronidazole will often cause stomach cramps, dizziness, headache, diarrhea, nausea or vomiting. If it causes numbness, tingling, or convulsions, you should check with your doctor immediately.


1The use of metronidazole against gastritis caused by Helicobacter pylori is a component of combination therapy used to treat the condition.

*The issue of resistance to metronidazole is currently a fairly minor concern, but some scientists worry that the widespread use of treatments which use only metronidazole will eventually lead to problems.

**I have recently been using computer simulations to research the mechanism by which metronidazole is reduced by TvFd. Much of the information I put in this writeup was taught me by my supervisor at the beginning of the project. I have not included specific details of this project because it would require a long explanation of some of the characteristics of TvFd, and that is not the subject of this writeup.

References, or just more reading:
http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202365.html

Petrin, D., K. Delgaty, R. Bhatt, and G. Garber. 1998. Clinical and microbiological aspects of Trichomonas vaginals. Clin. Microbol. Rev. 11:300-317.

or online at

http://cmr.asm.org/cgi/content/full/11/2/300

Sameuelson, John. 1999. Why Metronidazole Is Active against both Bacteria and Parasites. Antimicrob. Agents Chemother. 43: 1533-1541.

or online at

http://aac.asm.org/cgi/content/full/43/7/1533

These papers have their own references as well.

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