From the Guidelines
Rifampicin inhibits bacterial RNA synthesis by binding to the beta subunit of DNA-dependent RNA polymerase, preventing transcription initiation, as described in the study published in Otolaryngology--head and neck surgery 1. This mechanism blocks the synthesis of messenger RNA and protein production in bacteria, leading to cell death. The key aspects of rifampicin's mechanism of action (MOA) include:
- Binding to the β subunit on RNA polymerase
- Blocking RNA transcription (suppressing the initiation of chain formation)
- Resulting in a bactericidal effect
- Active against a variety of intracellular and extracellular microorganisms, including gram-positive and -negative bacteria, fungi, and parasites Rifampicin is particularly effective against mycobacteria, making it a cornerstone drug for tuberculosis treatment. It is typically administered at doses of 600mg daily for adults (10mg/kg for children) as part of combination therapy to prevent resistance development, as noted in the guidelines for tuberculosis treatment 1. The drug's lipophilic properties allow it to penetrate tissues, cerebrospinal fluid, and even intracellular bacteria effectively. Rifampicin is bactericidal against dividing bacteria and has a sterilizing effect on semi-dormant bacterial populations with sporadic metabolic bursts. Its ability to kill these persistent bacteria contributes to its importance in shortening tuberculosis treatment duration. However, rifampicin is a potent inducer of cytochrome P450 enzymes, leading to numerous drug interactions that require careful monitoring when used in combination therapy, as highlighted in the study on concurrent administration of antiretroviral agents and rifamycins 1.
From the FDA Drug Label
Mechanism of Action Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.
The mechanism of action (MOA) of rifampicin is the inhibition of DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. It interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme 2.
From the Research
Mechanism of Action of Rifampicin
- Rifampicin inhibits bacterial RNA polymerase, the enzyme responsible for DNA transcription, by forming a stable drug-enzyme complex 3.
- The inhibitor binds in a pocket of the RNAP beta subunit deep within the DNA/RNA channel, but more than 12 A away from the active site 4.
- Rifampicin acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length 4.
- The binding of rifampicin to RNA polymerase holoenzyme inhibits its autorepressor activity, thus relieving the autorepression exerted possibly on the translation of rpoBC mRNA 5.
- The rifampicin-RNA polymerase complex functions as a positive effector stimulating the transcription of rpoBC genes 5.
Resistance to Rifampicin
- Bacterial resistance to rifampicin is caused by mutations leading to a change in the structure of the beta subunit of RNA polymerase 3.
- Such resistance is not an all-or-nothing phenomenon; rather, a large number of RNA polymerases with various degrees of sensitivity to rifampicin have been found 3.
- No strict correlation exists between enzyme sensitivity and MIC values, since inhibition of RNA synthesis does not always show up to the same extent in the two different test systems used for the determination of these values 3.
Effects of Rifampicin on Bacterial Cells
- Rifampicin treatment of Escherichia coli results in a 50% decrease in cell size due to a terminal cell division 6.
- There is also a 50% decrease in total RNA due mostly to a 90% decrease in 23S and 16S rRNA levels 6.
- Rifampicin-induced rRNA degradation occurs under different growth conditions and in different strain backgrounds 6.