Mechanism of action Binding of<unk>  in the active site of<unk> NA polymerase. Mutation of amino acids shown in<unk> ed are involved in<unk> esistance to the antibiotic.<unk>  inhibits bacterial DNA-dependent<unk> NA synthesis by inhibiting bacterial DNA-dependent<unk> NA polymerase. Crystal structure data and biochemical data suggest that<unk>  binds to the pocket of the<unk> NA polymerase β subunit within the DNA/RNA channel, but away from the active site. The inhibitor prevents<unk> NA synthesis by physically blocking elongation, and thus preventing synthesis of host bacterial proteins. By this "steric-occlusion" mechanism,<unk>  blocks synthesis of the second or third phosphodiester bond between the nucleotides in the<unk> NA backbone, preventing elongation of the 5' end of the<unk> NA transcript past more than 2 or 3 nucleotides. In a<unk> ecent study<unk>  was shown to bind to cytochrome P450<unk> eductase and alter its conformation as well as activity towards supporting metabolism of progesterone via CYP21A2. Mechanism of<unk> esistance<unk> esistance to<unk>  arises from mutations that alter<unk> esidues of the<unk>  binding site on<unk> NA polymerase,<unk> esulting in decreased affinity for<unk> .<unk> esistance mutations map to the<unk> poB gene, encoding the beta subunit of<unk> NA polymerase. The majority of<unk> esistance mutations in E. coli are in 3 clusters on<unk> poB. Cluster I is amino acids 509 to 533, cluster II is amino acids 563 to 572, and cluster III is amino acid 687. When describing mutations in<unk> poB in other species, the corresponding amino acid number in E. coli is usually used. In Mycobacterium tuberculosis, the majority of mutations leading to<unk> <unk> esistance are in cluster I, in a 81bp hotspot core<unk> egion called<unk> RDR for "rifampcin<unk> esistance determining<unk> egion". A change in amino acid 531 from serine to leucine arising from a change in the DNA sequence of TCG to TTG is the most common mutation. Tuberculosis<unk> esistance has also occurred due to mutations in the N-terminal<unk> egion of<unk> poB and cluster III. An alternative mechanism of<unk> esistance is through Arr-catalyzed ADP-ribosylation of<unk> . With the assistance of the enzyme Arr produced by the pathogen Mycobacterium smegmatis, ADP-ribose is added to<unk>  at one of its ansa chain hydroxy groups, thereby inactivating the drug.<unk> esistance in tuberculosis Mycobacterial<unk> esistance to<unk>  may occur alone or along with<unk> esistance to other first-line antitubercular drugs. Early detection of such multidrug or extensively drug-resistant tuberculosis is critical in improving patient outcomes by instituting appropriate second-line treatments, and in decreasing transmission of drug-resistant TB. Traditional methods of detecting<unk> esistance involve mycobacterial culture and drug susceptibility testing,<unk> esults of which could take up to 6 weeks. Xpert MTB/RIF assay is an automated test that can detect<unk> <unk> esistance, and also diagnose tuberculosis. A Cochrane<unk> eview updated in 2014 concluded that for<unk> <unk> esistance detection, Xpert MTB/RIF was accurate, that is (95%) sensitive and (98%) specific. Pharmacokinetics Orally administered<unk> <unk> esults in peak plasma concentrations in about 2–4 hours. 4-Aminosalicylic acid (another antituberculosis drug) significantly<unk> educes absorption of<unk> , and peak concentrations may be lower. If these two drugs must be used concurrently, they must be given separately, with an interval of 8 to 12 hours between administrations.<unk>  is easily absorbed from the gastrointestinal (GI) tract; its ester functional group is quickly hydrolyzed in bile, and it is catalyzed by a high pH and substrate-specific esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form,<unk>  is still a potent antibiotic; however, it can no longer be<unk> eabsorbed by the intestines and is eliminated from the body. Only about 7% of the administered drug is excreted unchanged in urine, though urinary elimination accounts for only about 30% of the drug excretion. About 60% to 65% is excreted through feces. The half-life of<unk> <unk> anges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it. Food consumption inhibits its absorption from the GI tract, and the drug is more quickly eliminated. When<unk>  is taken with a meal, its peak blood concentration falls by 36%. Antacids do not affect its absorption. The decrease in<unk>  absorption with food is sometimes enough to noticeably affect urine color, which can be used as a marker for whether or not a dose of the drug has been effectively absorbed. Distribution of the drug is high throughout the body, and<unk> eaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. Since the substance itself is<unk> ed, this high distribution is the<unk> eason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.
Rifampicin
Secnidazole
Safinamide
Pyrazinamide
Amifampridine
Amikacin
Fexinidazole
Tinidazole