Rifaximin Mechanism of Action
Rifaximin inhibits bacterial RNA synthesis by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking transcription and thereby preventing bacterial protein synthesis. 1
Primary Molecular Mechanism
Rifaximin binds specifically to the beta-subunit of bacterial DNA-dependent RNA polymerase, which blocks one of the steps in transcription, resulting in inhibition of bacterial protein synthesis and consequently inhibits bacterial growth 2
This binding mechanism suppresses the initiation of RNA chain formation, producing a bactericidal effect against susceptible organisms 1
The antimicrobial effect is relatively specific to bacterial organisms at usual doses, as mammalian RNA synthesis is not affected 1
Spectrum of Antimicrobial Activity
Rifaximin demonstrates broad antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative bacteria 1
The drug shows good activity against species of Staphylococcus, Streptococcus, Enterococcus, and diarrheagenic Escherichia coli (including enterotoxigenic and enteroaggregative strains) 2, 3
Activity is more limited against species of Enterobacteriaceae and invasive pathogens such as Campylobacter, Salmonella, and Shigella species 1, 3
Unique Pharmacological Properties
Rifaximin maintains high concentration levels in the intestine because it is not absorbed systemically, remaining in an active form until it is excreted 1
After oral administration, approximately 97% of rifaximin is recovered in feces, with minimal systemic absorption (mean plasma concentrations range from 2.4 to 4 ng/mL) 2
This lack of systemic absorption means rifaximin exerts its antimicrobial activity primarily in the intestinal tract, making it unsuitable for treating systemic bacterial infections 2
Resistance Mechanisms
Resistance to rifaximin is caused primarily by mutations in the rpoB gene, which changes the binding site on DNA-dependent RNA polymerase and decreases rifaximin binding affinity 2
Cross-resistance between rifaximin and other classes of antimicrobials has not been observed 2
Despite potential for resistance development, rifaximin demonstrates low microbial resistance in clinical practice compared to other antibiotics 4
Additional Mechanisms Beyond Antimicrobial Action
Rifaximin acts as a selective agonist of the pregnane X receptor (PXR), a nuclear receptor that regulates genes related to xenobiotic metabolism and drug detoxification 5, 6
Through PXR activation, rifaximin can elicit immunomodulatory effects by interacting with intracellular signaling cascades, including the nuclear factor kappa B and c-jun N-terminal kinase pathways 5
These PXR-dependent pathways may contribute to rifaximin's efficacy beyond simple antimicrobial effects, particularly in conditions like irritable bowel syndrome where the exact mechanism remains uncertain 1
Clinical Implications of Mechanism
The mechanism allows rifaximin to reduce ammonia-producing bacteria in the gut, which is the basis for its efficacy in hepatic encephalopathy 1
By modulating gut microbiota composition, rifaximin can restore gut microflora imbalance without significant systemic adverse effects 4, 7
The non-absorbable nature and intestinal-specific action provide an excellent safety profile compared to systemically absorbed antibiotics 1, 8