Rifampin isoniazid pyrazinamide

# Overview

## Rifampin
Rifampin (USAN) or Rifampicin (INN) is a bactericidal antibiotic drug of the rifamycin group.
Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.
It is a semisynthetic compound derived from Amycolatopsis rifamycinica  (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei).  Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).
In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Prof. Piero Sensi (1920-) and Dr. Maria Teresa Timbal (1925 - 1969) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs), they decided to call these compounds "rifamycins". After two years of attempts to obtain more stable semisynthetic products, a new molecule with high efficacy and good tolerability was produced in 1959 and was named "rifampicin".
Rifampicin is also known as rifaldazine, R/AMP, rofact (in Canada), and rifampin in the United States. There are various types of rifamycins from which this is derived, but the rifampicin form, with a 4-methyl-1-piperazinaminyl group, is by far the most clinically effective.

## Isoniazid
Isoniazid, also known as isonicotinylhydrazine (INH), is an organic compound that is the first-line medication in prevention and treatment of tuberculosis. The compound was first synthesized in the early 20th century, but its activity against tuberculosis was first reported in the early 1950s, and three pharmaceutical companies attempted unsuccessfully to simultaneously patent the drug (the most prominent one being Roche, which launched its version, Rimifon, in 1952). The drug was first tested at Many Farms, a Navajo community, due to the Navajo reservation's dire tuberculosis problem and the fact that the population was naive with respect to streptomycin, the main tuberculosis treatment at the time. With the introduction of isoniazid, a cure for tuberculosis was first considered reasonable.

## Pyrazinamide
Pyrazinamide is a drug used to treat tuberculosis.  The drug is largely bacteriostatic, but can be bacteriocidal on actively replicating tuberculosis bacteria.

# Category
Antimycobacterial

# US Brand Names
RIFATER

# FDA Package Insert
Description

# Mechanisms of Action

## Rifampin
Rifampin inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase.
Crystal structure data and biochemical data indicate that rifampicin binds to RNA polymerase at a site adjacent to the RNA polymerase active center and blocks RNA synthesis by physically preventing extension of RNA products beyond a length of 2-3 nucleotides ("steric-occlusion" mechanism).
Resistance to rifampicin arises from mutations that alter residues of the rifampicin binding site on RNA polymerase, resulting in decreased affinity for rifampicin.  Resistant mutations map to the rpoB gene, encoding RNA polymerase beta subunit.

## Isoniazid
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.  KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of isoniazid, including nitric oxide, which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.
Isoniazid is bactericidal to rapidly dividing mycobacteria, but is bacteriostatic if the mycobacteria are slow-growing.
Isoniazid inhibits the P450 system.

## Pyrazinamide
Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis.
Pyrazinamide diffuses into M. tuberculosis, where the enzyme pyrazinamidase converts pyrazinamide to the active form pyrazinoic acid.  Under acidic conditions, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate.  The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.
Pyrazinoic acid was thought to inhibit the enzyme fatty acid synthase (FAS) I, which is required by the bacterium to synthesise fatty acids although this has been discounted. It was also suggested that the accumulation of pyrazinoic acid disrupts membrane potential and interferes with energy production, necessary for survival of M. tuberculosis at an acidic site of infection. Further studies reproduced the results of FAS I inhibition as the putative mechanism first in whole cell assay of replicating M. tuberculosis bacilli which have shown that pyrazinoic acid and its ester inhibit the synthesis of fatty acids. This study was followed by in vitro assay of tuberculous FAS I enzyme that tested the activity with pyrazinamide, pyrazinoic acid and several classes of  pyrazinamide analogs. Pyrazinamide and its analogs inhibited the activity of purified FAS I. Pyrazinoic acid binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria.
Mutations in the pncA gene, which encodes a pyrazinamidase, is responsible for the appearance of most pyrazinamide resistant M. tuberculosis strains.  A few pyrazinamidase resistant strains with mutations in the rpsA gene have also been identified.