- Solithromycin: A Novel Fluoroketolide for the Treatment of Community-Acquired Bacterial Pneumonia. [Review]
- DDrugs 2016 Dec 1
- Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CAB...
Solithromycin is a novel fluoroketolide developed in both oral and intravenous formulations to address increasing macrolide resistance in pathogens causing community-acquired bacterial pneumonia (CABP). When compared with its macrolide and ketolide predecessors, solithromycin has several structural modifications which increase its ribosomal binding and reduce its propensity to known macrolide resistance mechanisms. Solithromycin, like telithromycin, affects 50S ribosomal subunit formation and function, as well as causing frame-shift errors during translation. However, unlike telithromycin, which binds to two sites on the ribosome, solithromycin has three distinct ribosomal binding sites. Its desosamine sugar interacts at the A2058/A2059 cleft in domain V (as all macrolides do), an extended alkyl-aryl side chain interacts with base pair A752-U2609 in domain II (similar to telithromycin), and a fluorine at C-2 of solithromycin provides additional binding to the ribosome. Studies describing solithromycin activity against Streptococcus pneumoniae have reported that it does not induce erm-mediated resistance because it lacks a cladinose moiety, and that it is less susceptible than other macrolides to mef-mediated efflux due to its increased ribosomal binding and greater intrinsic activity. Solithromycin has demonstrated potent in vitro activity against the most common CABP pathogens, including macrolide-, penicillin-, and fluoroquinolone-resistant isolates of S. pneumoniae, as well as Haemophilus influenzae and atypical bacterial pathogens. Solithromycin displays multi-compartment pharmacokinetics, a large volume of distribution (>500 L), approximately 67% bioavailability when given orally, and serum protein binding of 81%. Its major metabolic pathway appears to follow cytochrome P450 (CYP) 3A4, with metabolites of solithromycin undergoing biliary excretion. Its serum half-life is approximately 6-9 h, which is sufficient for once-daily administration. Pharmacodynamic activity is best described as fAUC0-24/MIC (the ratio of the area under the free drug concentration-time curve from 0 to 24 h to the minimum inhibitory concentration of the isolate). Solithromycin has completed one phase II and two phase III clinical trials in patients with CABP. In the phase II trial, oral solithromycin was compared with oral levofloxacin and demonstrated similar clinical success rates in the intention-to-treat (ITT) population (84.6 vs 86.6%). Clinical success in the clinically evaluable patients group was 83.6% of patients receiving solithromycin compared with 93.1% for patients receiving levofloxacin. In SOLITAIRE-ORAL, a phase III trial which assessed patients receiving oral solithromycin or oral moxifloxacin for CABP, an equivalent (non-inferior) early clinical response in the ITT population was demonstrated for patients receiving either solithromycin (78.2%) or moxifloxacin (77.9%). In a separate phase III trial, SOLITAIRE-IV, patients receiving intravenous-to-oral solithromycin (79.3%) demonstrated non-inferiority as the primary outcome of early clinical response in the ITT population compared with patients receiving intravenous-to-oral moxifloxacin (79.7%). Overall, solithromycin has been well tolerated in clinical trials, with gastrointestinal adverse events being most common, occurring in approximately 10% of patients. Transaminase elevation occurred in 5-10% of patients and generally resolved following cessation of therapy. None of the rare serious adverse events that occurred with telithromycin (i.e., hepatotoxicity) have been noted with solithromycin, possibly due to the fact that solithromycin (unlike telithromycin) does not possess a pyridine moiety in its chemical structure, which has been implicated in inhibiting nicotinic acetylcholine receptors. Because solithromycin is a possible substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp), it may display drug interactions similar to macrolides such as clarithromycin. Overall, the in vitro activity, clinical efficacy, tolerability, and safety profile of solithromycin demonstrated to date suggest that it continues to be a promising treatment for CABP.
- Distribution and morphology of cholinergic cells in the branchial epithelium of zebrafish (Danio rerio). [Journal Article]
- CTCell Tissue Res 2016 Dec 2
- Acetylcholine is an excitatory neurotransmitter important for oxygen sensing in mammals. A cholinergic mechanism in the fish gill has been implicated in the hyperventilatory response to acute hypoxia...
Acetylcholine is an excitatory neurotransmitter important for oxygen sensing in mammals. A cholinergic mechanism in the fish gill has been implicated in the hyperventilatory response to acute hypoxia; however, the identity and distribution of acetylcholine-containing cells in the gills is poorly defined. We test the hypothesis that cholinergic cells are present in the gill filament epithelium in zebrafish (Danio rerio), a model vertebrate for which oxygen chemoreceptors are well characterized, and that these cells would receive nervous innervation. Using immunohistochemistry and confocal microscopy, we observed 10.2 ± 0.6 cells immunoreactive for the vesicular acetylcholine transporter (VAChT) on the efferent aspect of each gill filament, where a high density of serotonergic oxygen-sensitive neuroepithelial cells (NECs) were located. VAChT-positive cells of the efferent epithelium were positioned within 10 μm of NECs. On the afferent aspect of the gill filaments, VAChT-positive cells were greater in number (30.8 ± 3.1 per filament). On the efferent and afferent filament aspects, VAChT-positive cells did not contain serotonin, but did express choline acetyltransferase (ChAT), the enzyme that synthesizes ACh, and were often closely apposed to nerve fibers labeled with the neuronal marker, zn-12. We conclude that cholinergic cells in the zebrafish gills were present in the primary epithelium of gill filaments, and formed contacts with nerve fibers. These studies provide morphological evidence for the presence of a cholinergic system in the zebrafish gill. Such a pathway may contribute to the reflex hyperventilatory response during hypoxia.
- Levamisole: A positive allosteric modulator for the α3β4 nicotinic acetylcholine receptors prevents weight gain in CD-1 mice on a high fat diet. [Journal Article]
- CPCurr Pharm Des 2016 Dec 01
- Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the function of multiple neurotransmitter pathways throughout the central nervous system. This includes nAChRs found on the proopiomelanoc...
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the function of multiple neurotransmitter pathways throughout the central nervous system. This includes nAChRs found on the proopiomelanocortin neurons in the hypothalamus. Activation of these nAChRs by nicotine causes a decrease in consumption of food in rodents. In this study, we tested the effect of subtype selective allosteric modulators for nAChRs on the body weight of CD-1 mice. Levamisole, an allosteric modulator for the α3β4 subtype of nAChRs, prevented weight gain in mice that were fed a high fat diet. PNU-120596 and desformylflustrabromine are selective PAMs for the α7 and α4β2 nAChR, respectively. Both of these compounds failed to prevent weight gain in CD-1 mice. These results suggest that modulation of hypothalamic α3β4 nAChRs is an important factor in regulating food intake, and the PAMs for these receptors need further investigation as potential therapeutic agents for controlling weight gain.
- Nicotine Induces Podocyte Apoptosis through Increasing Oxidative Stress. [Journal Article]
- PlosPLoS One 2016; 11(12):e0167071
- CONCLUSIONS: Nicotine induces podocyte apoptosis through ROS generation and associated downstream MAPKs signaling. The present study provides insight into molecular mechanisms involved in smoking associated progression of chronic kidney disease.
- VAChT overexpression increases acetylcholine at the synaptic cleft and accelerates aging of neuromuscular junctions. [Journal Article]
- SMSkelet Muscle 2016 Oct 5; 6(1):31
- CONCLUSIONS: The data presented in this manuscript demonstrate that increasing levels of ACh at the synaptic cleft promote degeneration of adult NMJs, contributing to age- and disease-related motor deficits. We thus propose that maintaining normal cholinergic signaling in muscles will slow degeneration of NMJs and attenuate loss of motor function caused by aging and neuromuscular diseases.
- Neurexin regulates nighttime sleep by modulating synaptic transmission. [Journal Article]
- SRSci Rep 2016 Dec 01; 6:38246
- Neurexins are cell adhesion molecules involved in synaptic formation and synaptic transmission. Mutations in neurexin genes are linked to autism spectrum disorders (ASDs), which are frequently associ...
Neurexins are cell adhesion molecules involved in synaptic formation and synaptic transmission. Mutations in neurexin genes are linked to autism spectrum disorders (ASDs), which are frequently associated with sleep problems. However, the role of neurexin-mediated synaptic transmission in sleep regulation is unclear. Here, we show that lack of the Drosophila α-neurexin homolog significantly reduces the quantity and quality of nighttime sleep and impairs sleep homeostasis. We report that neurexin expression in Drosophila mushroom body (MB) αβ neurons is essential for nighttime sleep. We demonstrate that reduced nighttime sleep in neurexin mutants is due to impaired αβ neuronal output, and show that neurexin functionally couples calcium channels (Cac) to regulate synaptic transmission. Finally, we determine that αβ surface (αβs) neurons release both acetylcholine and short neuropeptide F (sNPF), whereas αβ core (αβc) neurons release sNPF to promote nighttime sleep. Our findings reveal that neurexin regulates nighttime sleep by mediating the synaptic transmission of αβ neurons. This study elucidates the role of synaptic transmission in sleep regulation, and might offer insights into the mechanism of sleep disturbances in patients with autism disorders.
- Neonicotinoid-induced impairment of odour coding in the honeybee. [Journal Article]
- SRSci Rep 2016 Dec 01; 6:38110
- Exposure to neonicotinoid pesticides is considered one of the possible causes of honeybee (Apis mellifera) population decline. At sublethal doses, these chemicals have been shown to negatively affect...
Exposure to neonicotinoid pesticides is considered one of the possible causes of honeybee (Apis mellifera) population decline. At sublethal doses, these chemicals have been shown to negatively affect a number of behaviours, including performance of olfactory learning and memory, due to their interference with acetylcholine signalling in the mushroom bodies. Here we provide evidence that neonicotinoids can affect odour coding upstream of the mushroom bodies, in the first odour processing centres of the honeybee brain, i.e. the antennal lobes (ALs). In particular, we investigated the effects of imidacloprid, the most common neonicotinoid, in the AL glomeruli via in vivo two-photon calcium imaging combined with pulsed odour stimulation. Following acute imidacloprid treatment, odour-evoked calcium response amplitude in single glomeruli decreases, and at the network level the representations of different odours are no longer separated. This demonstrates that, under neonicotinoid influence, olfactory information might reach the mushroom bodies in a form that is already incorrect. Thus, some of the impairments in olfactory learning and memory caused by neonicotinoids could, in fact, arise from the disruption in odor coding and olfactory discrimination ability of the honey bees.
- Variant Aldehyde Dehydrogenase 2 (ALDH2*2) in East Asians Interactively Exacerbates Tobacco Smoking Risk for Coronary Spasm - Possible Role of Reactive Aldehydes. [Journal Article]
- CJCirc J 2016 Nov 29
- CONCLUSIONS: ALDH2*2synergistically exacerbates TS risk for CSA, probably through aldehydes.
- Block of nicotinic acetylcholine receptors by philanthotoxins is strongly dependent on their subunit composition. [Journal Article]
- SRSci Rep 2016 Nov 30; 6:38116
- Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve ...
Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes. Whole-cell currents in response to application of acetylcholine alone or co-applied with PhTX analogue were studied by using two-electrode voltage-clamp. α3β4 nAChRs were most sensitive to PhTX-343 (IC50 = 12 nM at -80 mV) with α4β4, α4β2, α3β2, α7 and α1β1γδ being 5, 26, 114, 422 and 992 times less sensitive. In contrast α1β1γδ was most sensitive to PhTX-12 along with α3β4 (IC50 values of 100 nM) with α4β4, α4β2, α3β2 and α7 being 3, 3, 26 and 49 times less sensitive. PhTX-343 inhibition was strongly voltage-dependent for all subunit combinations except α7, whereas this was not the case for PhTX-12 for which weak voltage dependence was observed. We conclude that PhTX-343 mainly acts as an open-channel blocker of nAChRs with strong subtype selectivity.
New Search Next
- Nature nurtures the design of new semi-synthetic macrolide antibiotics. [Review]
- JAJ Antibiot (Tokyo) 2016 Nov 30
- Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to ov...
Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. Solithromycin is a fourth-generation macrolide that has a fluorine at the 2-position, and an alkyl-aryl side chain that is different from telithromycin. Solithromycin interacts at three sites on the bacterial ribosome, has activity against strains resistant to older macrolides (including telithromycin), and is mostly bactericidal. Pharmaceutical scientists involved in the development of macrolide antibiotics have learned from the teachings of Professor Satoshi Omura and progress in this field was not possible without his endeavors.The Journal of Antibiotics advance online publication, 30 November 2016; doi:10.1038/ja.2016.137.