Pathways

In E. coliK-12, two component systems (TCSs) sense and respond to changes in environmental conditions. Typically, a membrane associated sensor kinase autophosphorylates in response to an environmental signal. The sensor kinase then transfers a phosphoryl group to a response regulator (RR) which thus activated, effects a response. The majority of RRs in E. coli are transcription factors. The BaeS and BaeR proteins are respectively, the sensor kinase and response regulator of the E. coli BaeSR two-component system. The BaeSR TCS induces expression of spy in response to envelope stresses such as spheroblast formation or misfolded pilus subunits, leading to the suggestion that the BaeSR TCS is an envelope stress response pathway. baeS and baeR form an operon with the multidrug resistance cluster mdtABCD and BaeR binds to and stimulates the transcriptional activity of the mdtA promoter. Overexpression of BaeR results in increased resistance to novobiocin and deoxycholate, but this phenotype is not dependent on the presence of BaeS. (EcoCyc)

In E.coli K-12, two component systems (TCSs) are responsible for sensing and response to changes in environmental conditions. Sensor kinase response environmental signals by auto-phosphorylate on membrane, which transfer a phosphoryl group to a response regulator (RR) for activation. Signal transduction histidine-protein kinase (BaeS) is sensor kinase and transcriptional regulatory protein (BaeR) is the response regulator in the TCSs. BaeR overexpression may lead to greater resistance to novobiocin and deoxycholate.

Bafetinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Bafetinib is considered a second generation BCR-ABL inhibitor (Imatinib being the progenitor) that inhibits BCR-ABL activity by binding a highly conserved ATP binding site to effectively lock the tyrosine kinase in an inactive conformation. As a result, phosphate is unable to be transferred from ATP to activate oncogenic signalling cascades. For greater detail, refer to the pathway titled BCR-ABL Action in CML Pathogenesis. Bafetinib is able to bind ABL with greater affinity than Imatinib (25-55 times more potent). It is therefore administered to patients with Imatinib resistance. Notably, Bafetinib is ineffective against the T315I mutation in BCR-ABL, and further research is necessary.

Baloxavir marboxil is a polymerase acidic endonuclease inhibitor used to treat uncomplicated influenza A, B, and Avian. It is specifically a first-in-class cap-dependent endonuclease inhibitor. It is a prodrug of baloxavir with an improved absorption profile than its active metabolite due to the addition of a phenolic hydroxyl group to its structure. Influenza virus RNA polymerase is made up of three subunits: polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA). The PB2 subunit binds to the cap of host cellular pre-messenger RNA, which allows the polymerase acidic protein to cleave the capped pre-messenger RNA.This is the initial step of mRNA synthesis so viral mRNA transcription can occur. After administration, the prodrug baloxavir marboxil is almost completely hydrolyzed by esterases in the gastrointestinal lumen, intestinal epithelium, liver and blood to its active metabolite, baloxavir. Balaxovir selectively inhibits the polymerase acidic protein, which blocks the initiation of mRNA synthesis which prevents influenza virus proliferation.

Baloxavir marboxil is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Baloxavir marboxil passes through the liver and is then excreted from the body mainly through the kidney.

Balsalazide, brand name Colazal, is an aminosalicylate anti-inflammatory drug used in the treatment of mildly to moderately active ulcerative colitis. Balsalazide works by delivering its metabolite 9mesalazine) to the large intestine to act directly on ulcerative colitis. Mesalazine is also known as 5-aminosalicylic acid (5-ASA). Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction. The mechanism of action of 5-aminosalicylic acid is unknown. Like the other NSAIDs, it probably targets the prostaglandin G/H synthase-1 (COX-1) and prostaglandin G/H synthase-2 (COX-2) in the cyclooxygenase pathway. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain fibers. Salsalate inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Moreover, it is possible that this drug also inhibits the lipoxygenase pathway (catalyzes the formation of leukotrienes and hydroxyeicosatetraenoic acids from arachidonic acid and its metabolites) by inhibiting the enzyme named arachidonate 5-lipoxygenase.

Bamipine is a first-generation piperidine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Bamlanivimab, also known as LY-CoV555 or LY3819253, is a human IgG1K monoclonal antibody (mAb) against the SARS-CoV2 spike protein, called S. This drug was synthesized from the first blood samples of a patient who recovered from COVID-19 in the USA. This molecule is not approved by the FDA, but it is authorized under an Emergency Use Authorization (EUA) for the treatment of COVID-19 patients. X-ray crystallography and cryo-EM structural determination suggest that this molecule binds the receptor-binding domain (RBD) of the spike protein of CoV-19. This binding overlaps the ACE2 binding site. Bamlanivimab is available as an intravenous injection.