Browsing Pathways

Tigecycline is an intravenous antibiotic drug used to treat infections caused by a variety of gram-positive and gram-negative microorganisms including Mycoplasma pneumoniae, Pasteurella pestis, Escherichia coli, Haemophilus influenzae (respiratory infections), and Diplococcus pneumoniae. Tigecycline first clinically-available drug in the class of glycylcyclines antibiotics. Glycylcyclines are derived from tetracycline which are analogues are specifically designed to overcome tetracycline resistance mediated by acquired efflux pumps and/or ribosomal protection. In bacterial protein synthesis, transcription and translation occur in the cytoplasm. Tigecycline targets protein translation. Translation occurs using the bacterial 70S ribosome composed of a 50S and a 30S subunit. The ribosome has 3 binding sites, A (acceptor site), P (peptidyl site) and E (exit site). The charged tRNA with an amino acid attached (amino-acyl tRNA) binds to the A site. The P site binds to the tRNA holding the growing polypeptide chain and the E site binds to the uncharged tRNA.

Tigecycline is a glycylcycline, a class of antibiotics derived from tetracycline. Tigecycline has broad spectrum antibacterial abilities and is not susceptible to traditional tetracycline resistance mechanisms such as ribosomal protection and efflux by tetracycline-specific pumps. Tigecycline inhibits bacterial protein synthesis by binding to the A site of the 16s rRNA on the 30S ribosomal subunit. By binding to the A site, tigecycline prevents tRNA from docking onto the 16S rRNA with it’s codon ultimately halting the addition of amino acids to elongate peptide chains used in protein structures.

Ticlopidine, marketed as Ticlid, is an antiplatelet drug that targets the P2Y12 receptor of platelets. Ticlopidine is taken orally and is a prodrug that must be metabolically activated before it can be effective. It first enters the liver and enters the endoplasmic reticulum where it is metabolized to form the active metabolite. First, it is catalyzed by cytochromes P450 2C19, 2B6 and 1A2 into 2-oxoclopidogrel. Secondly, it is processed by cytochromes P450 2B6, 2C9, 2C19, 3A4, 3A5, and serum paraoxonase/arylesterase 1 into the active metabolite of clopidogrel. The active metabolite of clopidogrel then enters the blood stream, where it binds irreversibly to the P2Y purinoreceptor 12 on the surface of platelet cells, preventing ADP from binding to and activating it. Clopidogrel prevents the activation of the Gi protein associated with the P2Y12 receptor from inactivating adenylate cyclase in the platelet, leading to a buildup of cAMP. This cAMP then activates calcium efflux pumps, preventing calcium buildup in the platelet, which would cause activation, and later, aggregation.