Metronidazole (Flagyl): Definition, Uses and Research

Is metronidazole an antibiotic?

Metronidazole (MTZ), an antibiotic derived from Streptomyces, was first marketed in the United States under the brand name Flagel, and later sold globally by Sanofi-Aventis as Flagyl, along with a number of generic manufacturers. Metronidazole is a representative drug of nitroimidazole, which has broad-spectrum anti-anaerobic bacteria and antigenic insects and is mainly used in clinical prevention and treatment of infection caused by anaerobic bacteria.

Nitroimidazole antibiotics at BOC Sciences

Antibiotic production services at BOC Sciences

What is metronidazole used for?

Metronidazole has been used since the 1960s to treat trichomoniasis vaginalis, a common sexually transmitted infection caused by trichomonas vaginalis. It was subsequently shown to be effective against parasitic infections such as amebic dysentery and giardiasis. These parasitic infections are very common in some areas, and the advent of metronidazole has greatly improved the effectiveness of treatment for these diseases. In addition to the above-mentioned parasitic infections, metronidazole is used to treat intra-abdominal infections caused by anaerobic bacteria, skin and soft tissue infections, gynecological infections, and certain central nervous system infections. Metronidazole is also a key treatment for Helicobacter pylori infection, one of the main causes of gastritis and stomach ulcers.

Mechanism of action of metronidazole

The mechanism of action of metronidazole is the key to its selective antibacterial activity. The antimicrobial mechanism of metronidazole consists of two processes: (a) reduction-activation process; (b) Restore the inactivation process. Once metronidazole (I) enters the bacteria, it undergoes a series of transformations. It first becomes an unstable free radical (II) and then may become various intermediates (III-VII). Specifically, metronidazole enters the bacteria and is reduced by reductase within the bacteria. This process acts like charging metronidazole, turning it into a super active free radical. These free radicals can attack the bacteria's DNA, proteins and other important structures, causing the bacteria to be unable to replicate and survive, and eventually die. Interestingly, this process only works well in the absence of oxygen. In the absence of oxygen, metronidazole can be effectively activated, releasing free radicals that damage bacterial DNA. In the aerobic environment, the redox state of bacteria and cells is different, and the presence of oxygen will compete with metronidazole for electrons, thus hindering the reduction process of drugs and reducing the generation of active free radicals. In summary, the reason why metronidazole is only effective against anaerobic bacteria is that its mechanism of action is closely related to the REDOX state and metabolic environment of bacteria.

The antimicrobial mechanism of metronidazole. (Dingsdag, S. A., 2018)

Metronidazole resistance

Over time, some bacteria have evolved resistance to metronidazole. They may reduce drug intake, increase drug excretion, or produce some special protein to neutralize the drug. Some bacteria produce a gene called nim, which encodes a special enzyme that turns metronidazole into a harmless substance. Other bacteria increase the number of effervescent pumps that flush out invading metronidazole molecules. Some bacteria even change the structure of their cell walls to make it harder for metronidazole to enter the cell.

Research of metronidazole

A new technology to degrade metronidazole

As a common agent with potential carcinogenicity, metronidazole is easy to accumulate in water environment, causing surface water and groundwater pollution. Due to its toxicity and high water solubility, the elimination of metronidazole from the environment has become an important problem. Therefore, Chen's team developed new technologies to effectively eliminate metronidazole pollution.

The degradation of metronidazole in aqueous solution was investigated by plasma-RDR. When the rotational speed increased from 0 to 500 r·min⁻¹, the degradation efficiency of metronidazole and the concentration of hydroxyl radicals produced in plasma-RDR increased by 41% and 2.954 mg·L⁻¹, respectively. Higher pulse repetition rate is conducive to improving the degradation efficiency, while higher initial concentration of metronidazole and larger solution volume are unfavorable to degradation. Based on the obtained experimental data, the degradation energy efficiency of metronidazole was calculated, and the correlation between energy efficiency and each operating parameter was proposed, and the deviation between the predicted value and the experimental data was within ±15%. In addition, the hydroxyl radical concentration increased by 0.671 mg·L⁻¹ within 120 min, and the degradation effect was significantly enhanced. The results of 3D fluorescence spectra and LC-MS showed that the conjugated heterocyclic structure of metronidazole was destroyed and small molecules were formed. Therefore, plasma-RDR collaboration with TiO2 catalysis is a promising method for antibiotic wastewater treatment.

Metronidazole nanoparticles reduce the pathogenicity of bacteria

Metronidazole is a drug used to treat intestinal infections caused by colorectal surgery. The traditional route of administration reduces its local effectiveness and has non-site effects. To overcome these limitations, this study proposes a drug delivery system (DDS) based on MTZ-loaded nanoparticles (NP) fixed on the surface of electrospun fiber webs. Different concentrations of MTZ (1, 2, 5 and 10 mg mL⁻¹) were loaded into chitosan-tripolyphosphate sodium NP. MTZ is loaded into the nanoparticles at the highest concentration, showing rapid release for the first 12 hours, followed by gradual release. The DDS was not toxic to human colon cells. When different bacterial strains were tested, significant reductions in E. coli and Staphylococcus aureus were observed, but there was no effect on Enterococcus faecalis. Therefore, this DDS has a high potential for local prevention of infection after colorectal suture.

Synthesis of metronidazole-Mn complexes

In recent years, it has been reported that metronidazole has drug resistance and adverse reactions in clinic. Modifying metronidazole to enhance its antibacterial action and reduce adverse reactions is a hot topic in the field of medicinal chemistry. Many metal ions combined with drugs can enhance the antibacterial ability of drugs. It has been reported that metronidazole metal complexes show strong antibacterial activity through the synergistic effect of metronidazole and metal ions. Manganese (Mn) plays an important role in biology as an enzyme activator and necessary cofactor, especially in bone development, cell structure, energy metabolism, mitochondrial REDOX and apoptosis. A number of in vitro studies have shown that Mn binding to DNA, RNA and ribosome results in protein transcription and translation disorders.

Yang et al., using metronidazole and manganese acetate as raw materials, synthesized the manganese complex of metronidazole, and characterized its structure by elemental analysis, IR, UV-Vis, conductivity, thermogravimetric methods, and studied the interaction between the complex and calf thymus DNA(ct-DNA). It is hoped to provide reference information for further research on the antimicrobial mechanism of metronidazole metal drugs. Based on the experimental results of spectrometric analysis and viscosity method, it can be concluded that the ligand and its manganese complex may interact with ct-DNA in a classical insertional manner. The interaction between ligand and ct-DNA is stronger than that of complex due to the better planarity of molecular structure of metronidazole ligand.

References

1. Dingsdag, S. A., Hunter, N. Metronidazole: an update on metabolism, structure–cytotoxicity and resistance mechanisms. Journal of Antimicrobial Chemotherapy. 2018, 73(2): 265-279.
2. Cai, Y., et al. An evaluation of metronidazole degradation in a plasma-assisted rotating disk reactor coupled with TiO2 in aqueous solution. Engineering. 2021, 7(11): 1603-1610.
3. Oliveira, A., et al. Metronidazole delivery nanosystem able to reduce the pathogenicity of bacteria in colorectal infection. Biomacromolecules. 2022, 23(6): 2415-2427.