scholarly journals Deep Functional Profiling Facilitates the Evaluation of the Antibacterial Potential of the Antibiotic Amicoumacin

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 157 ◽  
Author(s):  
Stanislav S. Terekhov ◽  
Anton S. Nazarov ◽  
Yuliana A. Mokrushina ◽  
Margarita N. Baranova ◽  
Nadezhda A. Potapova ◽  
...  
Keyword(s):  
Scale Production ◽  
Alternative Source ◽  
Lead Compounds ◽  
Functional Profiling ◽  
Microfluidic Assays ◽  
High Cytotoxicity ◽  
Mrsa Strains ◽  
Antibiotic Discovery ◽  
Essential Insight ◽  
Insight Into

The global spread of antibiotic resistance is forcing the scientific community to find new molecular strategies to counteract it. Deep functional profiling of microbiomes provides an alternative source for the discovery of novel antibiotic producers and probiotics. Recently, we implemented this ultrahigh-throughput screening approach for the isolation of Bacillus pumilus strains efficiently producing the ribosome-targeting antibiotic amicoumacin A (Ami). Proteomics and metabolomics revealed essential insight into the activation of Ami biosynthesis. Here, we applied omics to boost Ami biosynthesis, providing the optimized cultivation conditions for high-scale production of Ami. Ami displayed a pronounced activity against Lactobacillales and Staphylococcaceae, including methicillin-resistant Staphylococcus aureus (MRSA) strains, which was determined using both classical and massive single-cell microfluidic assays. However, the practical application of Ami is limited by its high cytotoxicity and particularly low stability. The former is associated with its self-lactonization, serving as an improvised intermediate state of Ami hydrolysis. This intramolecular reaction decreases Ami half-life at physiological conditions to less than 2 h, which is unprecedented for a terminal amide. While we speculate that the instability of Ami is essential for Bacillus ecology, we believe that its stable analogs represent attractive lead compounds both for antibiotic discovery and for anticancer drug development.

Applications of Molecular Docking

2016 ◽  
pp. 278-306
Author(s):  
Josephine Anthony ◽  
Vijaya Raghavan Rangamaran ◽  
Kumar T. Shivasankarasubbiah ◽  
Dharani Gopal ◽  
Kirubagaran Ramalingam
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Fatty Acid ◽  
Molecular Mechanisms ◽  
Fatty Acid Biosynthesis ◽  
Dynamics Simulation ◽  
Computational Techniques ◽  
Lead Compounds ◽  
Medical Interest ◽  
Insight Into

Computational tools have extended their reach into different realms of scientific research. Often coupled with molecular dynamics simulation, docking provides comprehensive insight into molecular mechanisms of biological processes. Influence of molecular docking is highly experienced in the field of structure based drug discovery, wherein docking is vital in validating novel lead compounds. The significance of molecular docking is also understood in several environmental and industrial research, in order to untangle the interactions among macromolecules of non-medical interest. Various processes such as bioremediation (REMEDIDOCK), nanomaterial interactions (NANODOCK), nutraceutical interactions (NUTRADOCK), fatty acid biosynthesis (FADOCK), and antifoulers interactions (FOULDOCK) find the application of molecular docking. This chapter emphasizes the involvement of computational techniques in the aforementioned fields to expand our knowledge on macromolecular interacting mechanisms.

Liposomes

2017 ◽  
pp. 52-87
Author(s):  
Mangal Shailesh Nagarsenker ◽  
Megha Sunil Marwah
Keyword(s):  
Quality Control ◽  
Large Scale ◽  
Clinical Success ◽  
Scale Production ◽  
Large Scale Production ◽  
Diagnostic Applications ◽  
Set Up ◽  
Insight Into ◽  
Characterisation Techniques

The science of liposomes has expanded in ambit from bench to clinic through industrial production in thirty years since the naissance of the concept. This chapter makes an attempt to bring to light the impregnable contributions of great researchers in the field of liposomology that has witnessed clinical success in the recent times. The journey which began in 1965 with the observations of Bangham and further advances made en route (targeting/stealthing of liposomes) along with alternative and potential liposome forming amphiphiles has been highlighted in this chapter. The authors have also summarised the conventional and novel industrially feasible methods used to formulate liposomes in addition to characterisation techniques which have been used to set up quality control standards for large scale production. Besides, the authors have provided with an overview of primary therapeutic and diagnostic applications and a brief insight into the in vivo behaviour of liposomes.

scholarly journals Chloroquine Urea Derivatives: Synthesis and Antitumor Activity in Vitro

2018 ◽  
Vol 68 (4) ◽  
pp. 471-483 ◽  
Author(s):  
Kristina Pavić ◽  
Zrinka Rajić ◽  
Zvonimir Mlinarić ◽  
Lidija Uzelac ◽  
Marijeta Kralj ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Anticancer Agents ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Urea Derivatives ◽  
Design Synthesis ◽  
Human Cancer Cell Lines ◽  
Lead Compounds ◽  
Insight Into

Abstract In the current paper, we describe the design, synthesis and antiproliferative screening of novel chloroquine derivatives with a quinoline core linked to a hydroxy or halogen amine through a flexible aminobutyl chain and urea spacer. Synthetic pathway leading to chloroquine urea derivatives 4-10 includes two crucial steps: i) synthesis of chloroquine benzotriazolide 3 and ii) formation of urea derivatives through the reaction of compound 3 with the corresponding amine. Testing of antiproliferative activity against four human cancer cell lines revealed that chloroquine urea derivatives 9 and 10 with aromatic moieties show activity at micromolar concentrations. Therefore, these molecules represent interesting lead compounds that might provide an insight into the design of new anticancer agents.

scholarly journals Use of Permanent Wall-Deficient Cells as a System for the Discovery of New-to-Nature Metabolites

2020 ◽  
Vol 8 (12) ◽  
pp. 1897
Author(s):  
Shraddha Shitut ◽  
Güniz Özer Bergman ◽  
Alexander Kros ◽  
Daniel E. Rozen ◽  
Dennis Claessen
Keyword(s):  
Cell Wall ◽  
Secondary Metabolites ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Biosynthetic Gene Clusters ◽  
Microbial Cell Factories ◽  
Cell Factories ◽  
Genome Recombination ◽  
Antibiotic Discovery ◽  
Insight Into

Filamentous actinobacteria are widely used as microbial cell factories to produce valuable secondary metabolites, including the vast majority of clinically relevant antimicrobial compounds. Secondary metabolites are typically encoded by large biosynthetic gene clusters, which allow for a modular approach to generating diverse compounds through recombination. Protoplast fusion is a popular method for whole genome recombination that uses fusion of cells that are transiently wall-deficient. This process has been applied for both inter- and intraspecies recombination. An important limiting step in obtaining diverse recombinants from fused protoplasts is regeneration of the cell wall, because this forces the chromosomes from different parental lines to segregate, thereby preventing further recombination. Recently, several labs have gained insight into wall-deficient bacteria that have the ability to proliferate without their cell wall, known as L-forms. Unlike protoplasts, L-forms can stably maintain multiple chromosomes over many division cycles. Fusion of such L-forms would potentially allow cells to express genes from both parental genomes while also extending the time for recombination, both of which can contribute to an increased chemical diversity. Here, we present a perspective on how L-form fusion has the potential to become a platform for novel compound discovery and may thus help to overcome the antibiotic discovery void.

Skin-interfaced microfluidic devices with one-opening chambers and hydrophobic valves for sweat collection and analysis

Lab on a Chip ◽  
2020 ◽  
Vol 20 (15) ◽  
pp. 2635-2645 ◽  
Author(s):  
Yingxue Zhang ◽  
Yao Chen ◽  
Jielong Huang ◽  
Yangchengyi Liu ◽  
Jinfeng Peng ◽  
...  
Keyword(s):  
Microfluidic Devices ◽  
Microfluidic Platforms ◽  
Sweat Loss ◽  
Essential Insight ◽  
Insight Into ◽  
Sweat Collection

Soft, skin-interfaced microfluidic platforms are capable of capturing, storing, and assessing sweat chemistry and total sweat loss, which provides essential insight into human physiological health.

scholarly journals Preclinical Characterization of Naturally Occurring Polyketide Cyclophilin Inhibitors from the Sanglifehrin Family

2011 ◽  
Vol 55 (5) ◽  
pp. 1975-1981 ◽  
Author(s):  
Matthew A. Gregory ◽  
Michael Bobardt ◽  
Susan Obeid ◽  
Udayan Chatterji ◽  
Nigel J. Coates ◽  
...  
Keyword(s):  
Large Scale ◽  
Scale Production ◽  
Subgenomic Replicon ◽  
Isomerase Activity ◽  
Lead Compounds ◽  
Naturally Occurring ◽  
Large Scale Production ◽  
Pharmacokinetic Properties ◽  
Biosynthetic Engineering

ABSTRACTCyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC50s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability (F< 4%) and low solubility (<25 μM), although the half-lives (t1/2) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long (t1/2> 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.

scholarly journals Distribution of Fusidic Acid Resistance Determinants in Methicillin-ResistantStaphylococcus aureus

2010 ◽  
Vol 55 (3) ◽  
pp. 1173-1176 ◽  
Author(s):  
F. B. McLaws ◽  
A. R. Larsen ◽  
R. L. Skov ◽  
I. Chopra ◽  
A. J. O'Neill
Keyword(s):  
Fusidic Acid ◽  
Drug Target ◽  
Horizontal Transmission ◽  
Acid Resistance ◽  
Limited Data ◽  
Genetic Lineages ◽  
Resistance Determinants ◽  
Resistant Strains ◽  
Mrsa Strains ◽  
Insight Into

ABSTRACTThe prevalence of resistance to fusidic acid in clinical isolates ofStaphylococcus aureus, including methicillin-resistantS. aureus(MRSA), has increased in the past 2 decades. However, there are limited data regarding the relative importance in this process of the different staphylococcal determinants that mediate resistance to fusidic acid. Furthermore, the roles played by clonal dissemination of fusidic acid-resistant strains versus horizontal transmission of fusidic acid resistance determinants have not been investigated in detail. To gain insight into both issues, we examined fusidic acid resistance in 1,639 MRSA isolates collected in Denmark between 2003 and 2005. Resistance to fusidic acid (MIC, >1 μg/ml) was exhibited by 291 (17.6%) isolates. For the majority of these isolates (∼87%), resistance was attributed to carriage offusBorfusC, while the remainder harbored mutations in the gene (fusA) encoding the drug target (EF-G). The CC80-MRSA-IV clone carryingfusBaccounted for ∼61% of the resistant isolates in this collection, while a single CC5 clone harboringfusCrepresented ∼12% of the resistant strains. These findings emphasize the importance of clonal dissemination of fusidic acid resistance within European MRSA strains. Nonetheless, the distribution offusBandfusCacross several genetic lineages, and their presence on multiple genetic elements, indicates that horizontal transmission of fusidic acid resistance genes has also played an important role in the increasing prevalence of fusidic acid resistance in MRSA.

scholarly journals Versatility of 7-Substituted Coumarin Molecules as Antimycobacterial Agents, Neuronal Enzyme Inhibitors and Neuroprotective Agents

2017 ◽  
Author(s):  
Erika Kapp ◽  
Hanri Visser ◽  
Samantha L. Sampson ◽  
Sarel F. Malan ◽  
Elizabeth M. Streicher ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Neuroblastoma Cells ◽  
Antimycobacterial Activity ◽  
Tuberculosis H37rv ◽  
Neuroprotective Agents ◽  
Human Neuroblastoma ◽  
Lead Compounds ◽  
Antimycobacterial Agents ◽  
Insight Into

An in vitro medium-throughput screen using M. tuberculosis H37Rv was employed to screen an in-house library of structurally diverse compounds for antimycobacterial activity. &nbsp;From this initial screen, eleven 7-substituted coumarin derivatives with confirmed monoamine oxidase-B and cholinesterase inhibitory activities, demonstrated growth inhibition of more than 50% at a 50 &micro;M concentration.&nbsp; This prompted further exploration of all the 7-substituted coumarins in our library, nineteen in total, as potential antimycobacterial agents. Four derivatives showed promising antimycobacterial activity with MIC99 values of 8.31 &ndash; 29.70 &micro;M and 44.15 &ndash; 57.17 &micro;M on M. tuberculosis H37Rv in independent assays using Gaste-Fe and 7H9 + OADC media, respectively.&nbsp; &nbsp;These compounds were found to bind to albumin which may explain the variations in MIC between the two assays. &nbsp;Preliminary antimycobacterial evaluation of moxifloxacin resistant M. tuberculosis show that these compounds are able to maintain their activity in fluoroquinolone resistant mycobacteria.&nbsp; &nbsp;Analysis of structure activity relationships for antimycobacterial versus neuronal enzyme inhibitory activity indicate that structural modification on position 4 and/or 7 of the coumarin scaffold may be utilized to improve selectivity towards either inhibition of neuronal enzymes or antimycobacterial effect.&nbsp; Cytotoxicity evaluations of the compounds indicate moderate cytotoxicity with slight selectivity towards mycobacteria.&nbsp; Further neuroprotective assays on SH-SY5Y human neuroblastoma cells indicate significant neuroprotection for selected compounds irrespective of their neuronal enzyme inhibitory properties.&nbsp; These coumarin molecules are thus interesting lead compounds that may provide insight into the design of new antimicrobacterial and/or neuroprotective agents.

scholarly journals Analysis of the Bacterial and Host Proteins along and across the Porcine Gastrointestinal Tract

Proteomes ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 4 ◽  
Author(s):  
Johanna Tröscher-Mußotter ◽  
Bruno Tilocca ◽  
Volker Stefanski ◽  
Jana Seifert
Keyword(s):  
Gastrointestinal Tract ◽  
Feed Efficiency ◽  
Short Chain Fatty Acids ◽  
Intestinal Microbiome ◽  
Farm Animals ◽  
Host Proteins ◽  
Functional Profiling ◽  
Functional Analyses ◽  
Bacterial Groups ◽  
Insight Into

Pigs are among the most important farm animals worldwide and research to optimize their feed efficiency and improve their welfare is still in progress. The porcine intestinal microbiome is so far mainly known from sequencing-based studies. Digesta and mucosa samples from five different porcine gastrointestinal tract sections were analyzed by metaproteomics to obtain a deeper insight into the functions of bacterial groups with concomitant analyses of host proteins. Firmicutes (Prevotellaceae) dominated mucosa and digesta samples, followed by Bacteroidetes. Actinobacteria and Proteobacteria were much higher in abundance in mucosa compared to digesta samples. Functional profiling reveals the presence of core functions shared between digesta and mucosa samples. Protein abundances of energy production and conversion were higher in mucosa samples, whereas in digesta samples more proteins were involved in lipid transport and metabolism; short-chain fatty acids production were detected. Differences were also highlighted between sections, with the small intestine appearing more involved in carbohydrate transport and metabolism than the large intestine. Thus, this study produced the first functional analyses of the porcine GIT biology, discussing the findings in relation to expected bacterial and host functions.

Double-edged Role of KNa Channels in Brain Tuning: Identifying Epileptogenic Network Micro-Macro Disconnection

2021 ◽  
Vol 19 ◽  
Author(s):  
Ru Liu ◽  
Lei Sun ◽  
Yunfu Wang ◽  
Meng Jia ◽  
Qun Wang ◽  
...  
Keyword(s):  
Potential Role ◽  
Physiological Condition ◽  
Seizure Models ◽  
The Central Nervous System ◽  
Patients With Epilepsy ◽  
Essential Insight ◽  
Potential Threshold ◽  
Different Levels ◽  
Insight Into

: Epilepsy is commonly recognized as a disease driven by generalized hyperexcited and hypersynchronous neural activity. Sodium-activated potassium channels (KNa channels), which are encoded by the Slo 2.2 and Slo 2.1 genes, are widely expressed in the central nervous system and considered as “brakes” to adjust neuronal adaptation through regulating action potential threshold or after-hyperpolarization under physiological condition. However, the variants in KNa channels, especially gain-of-function variants, have been found in several childhood epileptic conditions. Most previous studies focused on mapping the epileptic network on the macroscopic scale while ignoring the value of microscopic changes. Notably, paradoxical role of KNa channels working on individual neuron/microcircuit and the macroscopic epileptic expression highlights the importance of understanding epileptogenic network through combining microscopic and macroscopic methods. Here, we first illustrated the molecular and physiological function of KNa channels on preclinical seizure models and patients with epilepsy. Next, we summarized current hypothesis on the potential role of KNa channels during seizures to provide essential insight into what emerged as a micro-macro disconnection at different levels. Additionally, we highlighted the potential utility of KNa channels as therapeutic targets for developing innovative anti-seizure medications.

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