Nitroimidazole: Definition, Mechanism and Uses

What is nitroimidazole?

Nitroimidazole antibiotics are a class of synthetic antibacterial agents with nitroimidazole ring structure and are mainly used to treat infections caused by anaerobic bacteria and protozoa. Nitroimidazole antibiotics have good antibacterial activity against a variety of gram-negative and gram-positive anaerobic bacteria. In vitro, it has good antibacterial activity against Gram-positive anaerobic bacteria such as Clostridium, Fungus, Peptococcus, Peptococcus, and against Gram-negative anaerobic bacteria such as Bacteroides (Bacteroides fragilis, Bacteroides geisii), Fusobacterium, Prevoella, etc. Most of the genera Defensiella, Lactobacillus, and Propionibacterium are resistant to nitroimidazole. Nitroimidazole antibiotics have no antibacterial activity against all aerobic bacteria. It has good anti-protozoal effect on Trichomonas vaginalis, Longiflagellates piriform, and Balantium coli. These drugs may cause disulfiram-like reactions when ingested with alcohol.

Nitroimidazole structure

The chemical structure of nitroimidazole antibiotics mainly consists of an imidazole ring and one or more nitro substituents (-NO2). Depending on the drug, the position and type of nitro group may vary, resulting in differences in structure and properties between various drugs. For example, 5-nitroimidazole drugs are widely used in medicine as fungicides and parasite control agents, while the biological activity of 4-nitroimidazole has been rarely reported. The structure of these compounds can be adjusted through different synthetic strategies to improve their antibacterial activity and possibly avoid bacterial resistance.

Nitroimidazole mechanism of action

Nitroimidazole is a classic class of antibiotics mainly used to treat infections caused by anaerobic or trace aerobic intestinal bacteria. However, the mechanism of action of nitroimidazole has not been fully understood, and no direct targets have been found. The current common explanation is that after drugs enter susceptible microbial cells, they need to reduce the nitro group to active form through the action of anaerobic bacteria or specific enzymes. This process is usually catalyzed by nitroreductases (NTRs), which use flavin monucleotides (FMN) or flavin adenine dinucleotides (FAD) as coenzymes and nicotinamide adenine dinucleotide (NADH) or NADPH as reducing agents. In an oxygen-free or oxygen-deficient environment and low redox potential, its nitro group is easily reduced by electron transfer proteins into active intermediates with cytotoxic effects, which covalently bonds with DNA, destroys the double helix structure of DNA, and leads to DNA chain breaks, thereby inhibiting nucleic acid synthesis by bacteria and parasites. These active molecules can also bind to proteins and other key molecules within cells, further inhibiting the metabolic function of microorganisms, thereby causing cell death. This biological activation is more pronounced in anaerobic bacteria because the negative redox potential of the cellular environment is necessary to reduce nitro groups, but the activity of nitroimidazole against aerobic bacteria is much reduced.

An indolin-2-one-substituted nitroimidazole antibiotic (compound 1) was recently reported, which has a submicron killing effect on aerobic bacteria, indicating that the antibiotic may have an unknown mechanism of action. Reinhardt et al. identified topoisomerase IV (parE) as a potential target of compound 1 through the active protein expression profiling (ABPP) experiment. Subsequent in vitro DNA decoralization experiments found that compound 1 could inhibit the activity of parE, and compound 2 formed after removal of the Michael receptor had no inhibitory effect. In addition, compound 1 still retained its inhibition of parE after being treated with nitroreductase NfsB, indicating that the inhibition was not dependent on nitro groups. The above results together demonstrate that compound 1 exhibits the activity of aerobic Staphylococcus aureus by inhibiting the key antibiotic target topoisomerase IV. The author also used cyclic voltammetry to find that compound 1 has a high redox potential, which makes the reactive species it forms difficult to quench, which may be the reason why it can remain active in an aerobic environment. This study explains the mechanism of action of indolin-2-one nitroimidazole and provides a basis for the application of nitroimidazole antibiotics to aerobic bacteria.

Identification of antibiotic action sites based on active protein expression profile (ABPP). (Reinhardt, T., 2022)

Nitroimidazole examples and uses

Metronidazole, tinidazole, and ormidazole are the first, second and third generation anti-anaerobic drugs used in clinical practice respectively. In 1978, WHO determined metronidazole as the basic and first choice for anti-anaerobic infections. Since then, a series of derivatives have been continuously developed.

Nitroimidazole antibiotics at BOC Sciences

Antibiotic production services at BOC Sciences

Metronidazole

Metronidazole is an antibiotic extracted from Streptomyces. In its early years, it was used to treat protozoal infections such as trichomoniasis, amoeba, and giardia. In the 1960s, it was found to have strong antibacterial effects on anaerobic bacteria. After its antibacterial effect, it is widely used to treat anaerobic bacteria infections and remains the drug of choice for anaerobic bacteria infections. It can be used for peptic ulcers related to Campylobacter pylori. Metronidazole can also inhibit the secretion of gastric acid and promote the healing of ulcers. It can also treat vaginitis, pelvic infections, brain abscesses and meningitis caused by anaerobic bacteria. Metronidazole has a half-life of 7-8 hours, a plasma protein binding rate of less than 5%, rapid and complete oral absorption, and a bioavailability of over 80%.

Tinidazole

Tinidazole is a second-generation nitroimidazole antibiotic, also known as 2-methyl-1-[2-(ethylsulfonyl) ethyl]-5-nitro-1H-imidazole. It was developed and marketed by Pfizer Company in the United Kingdom in 1982. Compared with the first-generation metronidazole, tinidazole has a broader antibacterial spectrum and better therapeutic effect. The mechanism of action of tinidazole on anaerobic bacteria is to inhibit bacterial DNA transcription and replication, prevent bacterial DNA synthesis, and thereby inhibit bacterial growth. For protozoa, it can inhibit its redox reaction, causing the DNA of protozoa to be broken, killing it. Tinidazole has a half-life of 12-14 hours, and its plasma protein binding rate is less than 12%. It is absorbed quickly and completely after oral administration. The blood concentration reaches a peak within 2-3 hours, and its bioavailability is high. Tinidazole is mainly used to treat respiratory infections caused by sensitive anaerobic bacteria, as well as trichomoniasis, giardia flagellosis, amoebiasis, etc.

Ornidazole

Ornidazole is a third-generation nitroimidazole antibiotic. The chemical name is 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole. It is a 5-nitroimidazole antibiotic. It is developed by Roche, Switzerland and launched in 1977. Ornidazole has a half-life of 14-15 hours, a plasma protein binding rate of less than 15%, and is rapidly absorbed orally. The peak blood concentration can be reached after 2 hours, and the bioavailability reaches 90%. Ornidazole is mainly used to treat various diseases caused by anaerobic infections, such as vaginal trichomoniasis, amoebiasis.

Secnidazole

The fourth-generation 5-nitroimidazole antibiotic has similar structure and pharmacological effects to metronidazole. The in vitro antigen spectrum of secnidazole is comparable to that of metronidazole, including vaginal trichomoniasis, amoebiasis, Trichomonas bovis, Giardia lamborica (Giardia duodenum, Giardia enterocinum). Secnidazole also has anti-anaerobic activity in vitro.

Reference

1. Reinhardt, T., et al. Indolin-2-one nitroimidazole antibiotics exhibit an unexpected dual mode of action. ACS Chemical Biology. 2022, 17(11): 3077-3085.