Mechanism of Action of Metronidazole
Metronidazole is a bactericidal nitroimidazole antibiotic that rapidly inhibits DNA replication in susceptible anaerobic bacteria and protozoa through reduction of its nitro group by intracellular electron transport proteins, forming toxic intermediates that damage DNA without causing strand breakage. 1, 2
Primary Mechanism Against Anaerobic Organisms
Metronidazole enters susceptible organisms through passive diffusion and undergoes reduction of its nitro group by ferredoxin or similar low-redox potential electron transport proteins present only in anaerobic and microaerophilic organisms. 3, 4
The reduced metronidazole forms reactive intermediates (nitro radical anions) that directly inhibit DNA synthesis by blocking DNA replication, causing immediate cessation of DNA synthesis within minutes of drug exposure. 2
Critically, metronidazole does NOT cause DNA strand breakage or nicking—the DNA remains structurally intact, and DNA polymerase enzyme activity is not directly inhibited. 2
RNA and protein synthesis continue at normal linear rates for at least 60 minutes after metronidazole exposure, demonstrating that DNA replication inhibition is the primary lethal mechanism, not general metabolic disruption. 2
Spectrum of Activity
Metronidazole is bactericidal at concentrations equal to or slightly higher than minimal inhibitory concentrations (typically ≤1 mcg/mL for susceptible organisms), distinguishing it from most other antimicrobials which are bacteriostatic. 1, 4
The drug is highly active against obligate anaerobes including Bacteroides fragilis group, Fusobacterium species, Clostridium species, Peptostreptococcus species, and Peptococcus niger. 1, 3
Metronidazole possesses direct trichomonacidal activity against Trichomonas vaginalis and amebacidal activity against Entamoeba histolytica and Giardia lamblia through the same DNA-damaging mechanism. 1, 4
Facultative anaerobes and obligate aerobes are resistant because they lack the low-redox potential electron transport proteins necessary to reduce metronidazole to its active toxic form. 1, 3
Additional Mechanisms in Specific Conditions
In rosacea treatment, topical metronidazole inhibits inflammatory mediators generated by neutrophils, providing anti-inflammatory effects beyond its antimicrobial action. 5
Against Helicobacter pylori, metronidazole contributes to eradication when combined with acid suppression and other antibiotics, though resistance is increasingly common. 3
Critical Clinical Pitfalls
Metronidazole has NO clinically relevant activity against facultative anaerobes or aerobic organisms—do not use as monotherapy for mixed aerobic-anaerobic infections without adding coverage for aerobes. 1, 3
Topical metronidazole gel achieves inadequate tissue concentrations for systemic infections and has <50% efficacy for trichomoniasis—only oral or intravenous formulations provide bactericidal concentrations in deep tissues. 6, 1
Resistance develops through alterations in the electron transport proteins that reduce metronidazole, making susceptibility testing important for treatment failures, particularly with Bacteroides fragilis and Trichomonas vaginalis. 1, 3