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International Journal of Molecular... Nov 2020Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other...
Synthesis and in Silico Modelling of the Potential Dual Mechanistic Activity of Small Cationic Peptides Potentiating the Antibiotic Novobiocin against Susceptible and Multi-Drug Resistant .
Cationic antimicrobial peptides have attracted interest, both as antimicrobial agents and for their ability to increase cell permeability to potentiate other antibiotics. However, toxicity to mammalian cells and complexity have hindered development for clinical use. We present the design and synthesis of very short cationic peptides (3-9 residues) with potential dual bacterial membrane permeation and efflux pump inhibition functionality. Peptides were designed based upon in silico similarity to known active peptides and efflux pump inhibitors. A number of these peptides potentiate the activity of the antibiotic novobiocin against susceptible and restore antibiotic activity against a multi-drug resistant strain, despite having minimal or no intrinsic antimicrobial activity. Molecular modelling studies, via docking studies and short molecular dynamics simulations, indicate two potential mechanisms of potentiating activity; increasing antibiotic cell permeation via complexation with novobiocin to enable self-promoted uptake, and binding the RND efflux pump. These peptides demonstrate potential for restoring the activity of hydrophobic drugs.
Topics: Antimicrobial Cationic Peptides; Chemistry Techniques, Synthetic; Drug Design; Drug Resistance, Multiple, Bacterial; Escherichia coli; Microbial Sensitivity Tests; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Novobiocin; Structure-Activity Relationship
PubMed: 33266278
DOI: 10.3390/ijms21239134 -
CNS Drug Reviews 2002LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2... (Review)
Review
LY404187 is a selective, potent and centrally active positive allosteric modulator of AMPA receptors. LY404187 preferentially acts at recombinant human homomeric GluR2 and GluR4 versus GluR1 and GluR3 AMPA receptors. In addition, LY404187 potentiates the flip splice variant of these AMPA receptors to a greater degree than the flop splice variant. In both recombinant and native AMPA receptors, potentiation by LY404187 displays a unique time-dependent growth that appears to involve a suppression of the desensitization process of these ion channels. LY404187 has been shown to enhance glutamatergic synaptic transmission both in vitro and in vivo. This augmentation of synaptic activity is due to the direct potentiation of AMPA receptor function, as well as an indirect recruitment of voltage-dependent NMDA receptor activity. Enhanced calcium influx through NMDA receptors is known to be a critical step in initiating long-term modifications in synaptic function (e.g., long-term potentiation, LTP). These modifications in synaptic function may be substrates for certain forms of memory encoding. Consistent with a recruitment of NMDA receptor activity, LY404187 has been shown to enhance performance in animal models of cognitive function requiring different mnemonic processes. These data suggest that AMPA receptor potentiators may be therapeutically beneficial for treating cognitive deficits in a variety of disorders, particularly those that are associated with reduced glutamatergic signaling such as schizophrenia. In addition, LY404187 has been demonstrated to be efficacious in animal models of behavioral despair that possess considerable predictive validity for antidepressant activity. Although the therapeutic efficacy of AMPA receptor potentiators in these and other diseases will ultimately be determined in the clinic, evidence suggests that the benefit of these compounds will be mediated by multiple mechanisms of action. These mechanisms include direct enhancement of AMPA receptor function, secondary mobilization of intracellular signaling cascades, and prolonged modulation of gene expression.
Topics: Action Potentials; Allosteric Regulation; Animals; Attention Deficit Disorder with Hyperactivity; Depression; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Hippocampus; Humans; Maze Learning; Memory Disorders; Mice; Prefrontal Cortex; Rats; Receptors, AMPA; Schizophrenia; Sulfonamides; Synaptic Transmission
PubMed: 12353058
DOI: 10.1111/j.1527-3458.2002.tb00228.x -
Drug Discoveries & Therapeutics Dec 2022A cell-based assay was conducted to screen microbial culture broths for potentiators of neutral lipid degradation in Chinese Hamster Ovary K1 cells. A total of 5,363...
A cell-based assay was conducted to screen microbial culture broths for potentiators of neutral lipid degradation in Chinese Hamster Ovary K1 cells. A total of 5,363 microbial cultures from fungi and actinomycetes were screened in this assay. Brefeldin A (1) from fungal cultures was found to promote the degradation of triacylglycerol (TG) with an EC of 2.6 µM. Beauveriolides I (2), III (3), beauverolides A (4), B (5), and K (6) from fungal cultures showed potentiating effect on cholesteryl ester (CE) degradation with ECs ranging from 0.02 to 0.13 µM. Among these compounds, 2 and 6 exhibited the strongest activities (EC, 0.02 µM). From actinomycete cultures, oxohygrolidin (7) (EC for TG and CE, > 1.7 and 0.8 µM, respectively) and hygrolidin (8) (EC for TG and CE, 0.08 and 0.004 µM, respectively) promoted degradation of CE more preferably than TG.
Topics: Cricetinae; Animals; Cricetulus; CHO Cells; Fungi; Lipids; Triglycerides
PubMed: 36450503
DOI: 10.5582/ddt.2022.01087 -
Journal of Cystic Fibrosis : Official... Sep 2021Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least...
Trikafta, the combination of elexacaftor (VX-445), tezacaftor (VX-661) and ivacaftor (VX-770), was approved for therapy of cystic fibrosis (CF) patients with at least one allele of the CFTR mutation F508del. While the corrector function of VX-445 is well established, here we investigated the putative potentiator activity of VX-445 alone and in combination with VX-770. Acute addition of VX-445 increased the VX-770-potentiated F508del- and G551D-CFTR current by ~24% and >70%, respectively, in human bronchial and nasal epithelia. Combinatorial profiling and cluster analysis of G551D- and G1244E-CFTR channel activation with potentiator pairs indicated a distinct VX-445 mechanism of action that is, at least, additive to previously identified potentiator classes, including the VX-770. Since VX-770 only partially normalizes the G551D-CFTR channel function and adult G551D patients still experience progressive loss of lung function, VX-445+VX-770 combination therapy could provide clinical benefit to CF patients with the G551D and other dual potentiator responsive mutants.
Topics: Cells, Cultured; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Genotype; Humans; Mutation; Nasal Mucosa; Pyrazoles; Pyridines; Pyrrolidines
PubMed: 33775603
DOI: 10.1016/j.jcf.2021.03.011 -
Antibiotics (Basel, Switzerland) Jul 2023Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic...
Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including . To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of . While all TOB-DEF conjugates were inactive against , the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, containing a C tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe concentration.
PubMed: 37627681
DOI: 10.3390/antibiotics12081261 -
Molecules (Basel, Switzerland) Feb 2022The burkholdines are a family of cyclic lipopeptides reported to exhibit antifungal activity. We synthesized a series of 18 burkholdine analogues in good yield by...
The burkholdines are a family of cyclic lipopeptides reported to exhibit antifungal activity. We synthesized a series of 18 burkholdine analogues in good yield by conventional Fmoc-SPPS followed by cyclization with DIPCI/HOBt in the solution phase. Although none of the synthesized peptides exhibited antifungal activity, several did potentiate the antibiotic effect of the antibiotic G418, including the Thr-bearing Bk analogue () and the tartaramide-bearing Bk analogue (). This work exemplifies the potential of burkholdine analogues as potentiating agents.
Topics: Antifungal Agents; Hydrophobic and Hydrophilic Interactions; Lipopeptides
PubMed: 35208979
DOI: 10.3390/molecules27041191 -
Mutation Research. Reviews in Mutation... Jul 2017Hydrogen peroxide (HO) is unique among general toxins, because it is stable in abiotic environments at ambient temperature and neutral pH, yet rapidly kills any type of... (Review)
Review
Hydrogen peroxide (HO) is unique among general toxins, because it is stable in abiotic environments at ambient temperature and neutral pH, yet rapidly kills any type of cells by producing highly-reactive hydroxyl radicals. This life-specific reactivity follows the distribution of soluble iron, Fe(II) (which combines with HO to form the famous Fenton's reagent),Fe(II) is concentrated inside cells, but is virtually absent outside them. Because of the immediate danger of HO, all cells have powerful HO scavengers, the equally famous catalases, which enable cells to survive thousand-fold higher concentrations of HO and, in combination with adequate movement of HO across membranes, make the killing HO concentrations virtually impractical to generate in vivo. And yet, low concentrations of HO are somehow used as an efficient biological weapon. Here we review several examples of how cells potentiate HO toxicity with other chemicals. At first, these potentiators were thought to simply inhibit catalases, but recent findings with cyanide suggest that potentiators mostly promote the other side of Fenton's reaction, recruiting iron from cell depots into stable DNA-iron complexes that, in the presence of elevated HO, efficiently break duplex DNA, pulverizing the chromosome. This multifaceted potentiation of HO toxicity results in robust and efficient killing.
Topics: Animals; Bacteria; Catalase; DNA; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Iron
PubMed: 28927535
DOI: 10.1016/j.mrrev.2016.08.006 -
Journal of Applied Physiology... Jan 2022Whole body vibration (WBV) is often applied as an alternative method for strength training or to prevent muscle force decrease. In this study, we evaluated the influence...
Whole body vibration (WBV) is often applied as an alternative method for strength training or to prevent muscle force decrease. In this study, we evaluated the influence of WBV on Ia monosynaptic input from muscle spindles because the tonic vibration reflex is responsible for the enhancement of muscle activity observed after WBV. The aim was to investigate whether repeated activation of muscle spindles during WBV may result in altered synaptic excitation of motoneurons. WBV was performed on adult male Wistar rats, 5 days/wk, for 5 wk, and each daily session consisted of four 30-s runs of vibration at 50 Hz. Fast-type medial gastrocnemius motoneurons were investigated intracellularly in deeply anesthetized animals in the experimental ( = 7, 34 motoneurons) and control ( = 7, 32 motoneurons) groups. Monosynaptic Ia excitatory postsynaptic potentials (EPSPs) were evoked by electrical stimulation of afferent fibers from the synergistic lateral gastrocnemius and soleus muscles. Data were analyzed using a mixed linear model. The central latencies of EPSPs were 0.45-0.9 ms with no differences in the mean values between the analyzed groups ( = 0.291). WBV induced an increase of the mean EPSP amplitude by 28% ( = 0.025), correlated with the resting membrane potential and input resistance, and a shortening of the mean EPSP rise time by 11% ( = 0.012). The potentiation of synaptic excitation of motoneurons was not accompanied by changes of passive membrane properties, pointing to synaptic plasticity. This indicates that WBV may support rehabilitation or training processes aimed at increasing muscle strength on the basis of increased motoneuronal drive. The study provides new information on neuronal plasticity following repeatedly exerted mechanical loading. We demonstrate in electrophysiological experiments on rat lumbar motoneurons that low-volume whole body vibration applied systematically for 5 wk potentiates synaptic excitation from primary muscle afferents. The adaptive changes are expressed by higher amplitudes and shorter rise times of monosynaptic EPSPs evoked in motoneurons of the vibrated group compared with the control.
Topics: Animals; Excitatory Postsynaptic Potentials; Male; Motor Neurons; Muscle, Skeletal; Rats; Rats, Wistar; Spinal Cord; Synapses; Vibration
PubMed: 34855524
DOI: 10.1152/japplphysiol.00519.2021 -
ACS Infectious Diseases Oct 2023By illuminating key 6-azasteroid-protein interactions in both () and the closely related model organism (), we sought to improve the antimycobacterial potency of...
By illuminating key 6-azasteroid-protein interactions in both () and the closely related model organism (), we sought to improve the antimycobacterial potency of 6-azasteroids and further our understanding of the mechanisms responsible for their potentiation of the antituberculosis drug bedaquiline. We selected a newly developed 6-azasteroid analog and an analog reported previously ( , (7), 1239-1251) to study their phenotypic effects on and , both alone and in combination with bedaquiline. The 6-azasteroid analog, 17β-[-(4-trifluoromethoxy-diphenylmethyl)carbamoyl]-6-propyl-azaandrostan-3-one, robustly potentiated bedaquiline-mediated antimycobacterial activity, with a nearly 8-fold reduction in bedaquiline minimal inhibitory concentration (85 nM alone versus 11 nM with 20 μM 6-azasteroid). This analog displayed minimal inhibitory activity against recombinant mycobacterial 3β-hydroxysteroid dehydrogenase, a previously identified target of several 6-azasteroids. Dose-dependent potentiation of bedaquiline by this analog reduced mycobacterial intracellular ATP levels and impeded the ability of to neutralize exogenous oxidative stress in culture. We developed two 6-azasteroid photoaffinity probes to investigate azasteroid-protein interactions in whole cells. Using bottom-up mass spectrometric profiling of the cross-linked proteins, we identified eight potential / protein targets for 6-azasteroids. The nature of these potential targets indicates that proteins related to oxidative stress resistance play a key role in the BDQ-potentiating activity of azasteroids and highlights the potential impact of inhibition of these targets on the generation of drug sensitivity.
Topics: Azasteroids; Antitubercular Agents; Mycobacterium tuberculosis; Bacterial Proteins; Mycobacterium marinum
PubMed: 37774412
DOI: 10.1021/acsinfecdis.3c00296 -
Frontiers in Pharmacology 2018The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride...
The psoralen-related compound, 4,6,4'-trimethylangelicin (TMA) potentiates the cAMP/PKA-dependent activation of WT-CFTR and rescues F508del-CFTR-dependent chloride secretion in both primary and secondary airway cells homozygous for the F508del mutation. We recently demonstrated that TMA, like lumacaftor (VX-809), stabilizes the first membrane-spanning domain (MSD1) and enhances the interface between NBD1 and ICL4 (MSD2). TMA also demonstrated anti-inflammatory properties, via reduction of IL-8 expression, thus making TMA a promising agent for treatment of cystic fibrosis. Unfortunately, TMA was also found to display potential phototoxicity and mutagenicity, despite the fact that photo-reactivity is absent when the compound is not directly irradiated with UVA light. Due to concerns about these toxic effects, new TMA analogs, characterized by identical or better activity profiles and minimized or reduced side effects, were synthesized by modifying specific structural features on the TMA scaffold, thus generating compounds with no mutagenicity and phototoxicity. Among these compounds, we found TMA analogs which maintained the potentiation activity of CFTR in FRT-YFP-G551D cells. Nanomolar concentrations of these analogs significantly rescued F508del CFTR-dependent chloride efflux in FRT-YFP-F508del, HEK-293 and CF bronchial epithelial cells. We then investigated the ability of TMA analogs to enhance the stable expression of varying CFTR truncation mutants in HEK-293 cells, with the aim of studying the mechanism of their corrector activity. Not surprisingly, MSD1 was the smallest domain stabilized by TMA analogs, as previously observed for TMA. Moreover, we found that TMA analogs were not effective on F508del-CFTR protein which was already stabilized by a second-site mutation at the NBD1-ICL4 interface. Altogether, our findings demonstrate that these TMA analogs mediate correction by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4.
PubMed: 30022950
DOI: 10.3389/fphar.2018.00719