Antitubercular potential and pH-driven mode of action of salicylic acid derivatives.

In the search for new antituberculosis drugs with novel mechanisms of action, we evaluated the antimycobacterial activity of a panel of eight phenolic acids against four pathogenic mycobacterial model species, including Mycobacterium tuberculosis. We demonstrated that salicylic acid (SA), as well as the iodinated derivatives 5-iodo-salicylic acid (5ISA) and 3,5-diiodo-salicylic acid (3,5diISA), displayed promising antitubercular activities. Remarkably, using a genetically encoded mycobacterial intrabacterial pH reporter, we describe for the first time that SA, 5ISA, 3,5diISA, and the anti-inflammatory drug aspirin (ASP) act by disrupting the intrabacterial pH homeostasis of M.

Fluorescence-based CRISPR interference system for controlled genetic repression and live single-cell imaging in mycobacteria.

In this research letter, we report the development and validation of a new subset of fluorescence-based CRISPR interference (CRISPRi) tools for our scientific community. The pJL series is directly derived from the original pIRL CRISPRi vectors and conserves all the elements to perform inducible targeted gene repression. These vectors carry two distinct fluorescent markers under the constitutive promoter psmyc to simplify the selection of recombinant clones.

Overview of alkyl quercetin lipophenol synthesis and its protective effect against carbonyl stress involved in neurodegeneration.

Oxidative stress and carbonyl stress resulting from the toxicity of small aldehydes are part of the detrimental mechanisms leading to neuronal cell loss involved in the progression of neurodegenerative diseases such as Alzheimer's disease. Polyunsaturated alkylated lipophenols represent a new class of hybrid molecules that combine the health benefits of anti-inflammatory omega-3 fatty acids with the anti-carbonyl and oxidative stress (anti-COS) properties of (poly)phenols in a single pharmacological entity. To investigate the therapeutic potential of quercetin-3-docosahexaenoic acid-7-isopropyl lipophenol in neurodegenerative diseases, three synthetic pathways using chemical or chemo-enzymatic strategies were developed to access milligram or gram scale quantities of this alkyl lipophenol.

A novel lipophenol quercetin derivative to prevent macular degeneration: Intravenous and oral formulations for preclinical pharmacological evaluation.

Drugs with properties against oxidative and carbonyl stresses are potential candidates to prevent dry age-related macular degeneration (Dry-AMD) and inherited Stargardt disease (STGD1). Previous studies have demonstrated the capacity of a new lipophenol drug: 3-O-DHA-7-O-isopropyl-quercetin (Q-IP-DHA) to protect ARPE19 and primary rat RPE cells respectively from A2E toxicity and under oxidative and carbonyl stress conditions. In this study, first, a new methodology has been developed to access gram scale of Q-IP-DHA.

Formulation and Evaluation of SNEDDS Loaded with Original Lipophenol for the Oral Route to Prevent Dry AMD and Stragardt's Disease.

Dry age-related macular degeneration (Dry AMD) and Stargardt's disease (STGD1) are common eye diseases, characterized by oxidative and carbonyl stress (COS)-inducing photoreceptor degeneration and vision loss. Previous studies have demonstrated the protective effect of photoreceptors after the intravenous administration of a new lipophenol drug, phloroglucinol-isopropyl-DHA (IP-DHA). In this study, we developed an oral formulation of IP-DHA (BCS Class IV) relying on a self-nanoemulsifying drug delivery system (SNEDDS).

Fatty Acid Hydroxytyrosyl Esters of Olive Oils Are Bioaccessible According to Simulated Gastrointestinal Digestion: Unraveling the Role of Digestive Enzymes on Their Stability.

Recently, new bioactive compounds were identified in olive oil, lipophenols, which are composed of a fatty acid (FA) and a phenolic core, such as HT (HT-FA). However, their bioaccessibility remains unknown. Thus, the present study uncovers the impact of the separate phases of gastrointestinal digestion on the release and stability of HT-FAs from oily matrices under simulated conditions.

New lipophenols prevent carbonyl and oxidative stresses involved in macular degeneration.

Dry age-related macular degeneration and Stargardt disease undergo a known toxic mechanism caused by carbonyl and oxidative stresses (COS). This is responsible for accumulation in the retinal pigment epithelium (RPE) of A2E, a main toxic pyridinium bis-retinoid lipofuscin component. Previous studies have shown that carbonyl stress in retinal cells could be reduced by an alkyl-phloroglucinol-DHA conjugate (lipophenol).

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus.

Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M.

Preclinical pharmacology of a lipophenol in a mouse model of light-induced retinopathy.

Environmental light has deleterious effects on the outer retina in human retinopathies, such as ABCA4-related Stargardt's disease and dry age-related macular degeneration. These effects involve carbonyl and oxidative stress, which contribute to retinal cell death and vision loss. Here, we used an albino Abca4 mouse model, the outer retina of which shows susceptibility to acute photodamage, to test the protective efficacy of a new polyunsaturated fatty acid lipophenol derivative.

Targeted Lipidomics Profiling Reveals the Generation of Hydroxytyrosol-Fatty Acids in Hydroxytyrosol-Fortified Oily Matrices: New Analytical Methodology and Cytotoxicity Evaluation.

Lipophenols have been stressed as an emerging class of functional compounds. However, little is known about their diversity. Thus, this study is aimed at developing a new method for the extraction, cleanup, and ultrahigh-performance liquid chromatography-electrospray ionization-triple quadrupole mass spectrometry (UHPLC-ESI-QqQ-MS/MS)-based analysis of the lipophenols derived from hydroxytyrosol (HT): α-linolenic (HT-ALA), linoleic acid (HT-LA), and oleic acid (HT-OA).

Isopropyl-phloroglucinol-DHA protects outer retinal cells against lethal dose of all-trans-retinal.

All-trans-retinal (atRAL) is a highly reactive carbonyl specie, known for its reactivity on cellular phosphatidylethanolamine in photoreceptor. It is generated by photoisomerization of 11-cis-retinal chromophore linked to opsin by the Schiff's base reaction. In ABCA4-associated autosomal recessive Stargardt macular dystrophy, atRAL results in carbonyl and oxidative stress, which leads to bisretinoid A2E, accumulation in the retinal pigment epithelium (RPE).

Combination of Lutein and Zeaxanthin, and DHA Regulated Polyunsaturated Fatty Acid Oxidation in HO-Stressed Retinal Cells.

Photochemical and oxidative damages in retinal pigment epithelial (RPE) cells are key events in the pathogenesis of age-related macular degeneration. Polyunsaturated fatty acids (PUFA) and carotenoids are rich in retinal cells, and under oxidative stress leads to oxidation and release lipid mediators. We evaluated the impact of carotenoids (lutein, zeaxanthin) and docosahexaenoic acid (DHA) supplementation on RPE cells under oxidative stress.

Bis-allylic Deuterated DHA Alleviates Oxidative Stress in Retinal Epithelial Cells.

Oxidative stress plays a crucial role in developing and accelerating retinal diseases including age-related macular degeneration (AMD). Docosahexaenoic acid (DHA, C22:6, n-3), the main lipid constituent of retinal epithelial cell membranes, is highly prone to radical and enzymatic oxidation leading to deleterious or beneficial metabolites for retinal tissue. To inhibit radical oxidation while preserving enzymatic metabolism, deuterium was incorporated at specific positions of DHA, resulting in D-DHA when incorporated at position 6 and D-DHA when incorporated at the 6,9 -allylic positions.

New Lipophenol Antioxidants Reduce Oxidative Damage in Retina Pigment Epithelial Cells.

Age-related macular degeneration (AMD) is a multifactorial pathology and its progression is exacerbated by oxidative stress. Oxidation and photo-oxidation reactions modify lipids in retinal cells, contribute to tissue injury, and lead to the formation of toxic adducts. In particular, autofluorescent pigments such as -retinylidene--retinylethanolamine (A2E) accumulate as lipofuscin in retinal pigment epithelial cells, contribute to the production of additional reactive oxygen species (ROS), and lead to cell degeneration.

LipG a bifunctional phospholipase/thioesterase involved in mycobacterial envelope remodeling.

Tuberculosis caused by is currently one of the leading causes of death from an infectious agent. The main difficulties encountered in eradicating this bacteria are mainly related to a very complex lipid composition of the bacillus cell wall, its ability to hide from the immune system inside the granulomas, and the increasing number of resistant strains. In this context, we were interested in the ( ) gene located upstream to the cluster which is described as being crucial for the production of cell wall components and required for the bacilli adaptation and survival in mouse macrophages Using biochemical experiments combined with the construction of deletion and overexpression mutant strains in , we found that LipG is a cytoplasmic membrane-associated enzyme that displays both phospholipase and thioesterase activities.

Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis.

A set of 19 oxadiazolone (OX) derivatives have been investigated for their antimycobacterial activity against two pathogenic slow-growing mycobacteria, Mycobacterium marinum and Mycobacterium bovis BCG, and the avirulent Mycobacterium tuberculosis (M. tb) mc6230. The encouraging minimal inhibitory concentrations (MIC) values obtained prompted us to test them against virulent M.

Resveratrol-Linoleate protects from exacerbated endothelial permeability via a drastic inhibition of the MMP-9 activity.

Gelatinolytic matrix metalloproteinases (MMP-2, -9) play a critical role not only in mammals physiology but also during inflammation and healing processes. The natural stilbenoid, resveratrol (RES), exhibits potent antioxidant effects, in a hormetic mode of action, and is known to inhibit MMP-9. However, RES administration exhibits major issues, including poor bioavailability and water solubility, hampering its potential therapeutic effect In the present study, we synthesized and evaluated five novel RES-lipid conjugates to increase their cell membrane penetration and improve their bioavailability.

Extra Virgin Olive Oil Reduced Polyunsaturated Fatty Acid and Cholesterol Oxidation in Rodent Liver: Is This Accounted for Hydroxytyrosol-Fatty Acid Conjugation?

The effects of extra virgin olive oil (EVOO) and carbon tetrachloride (CCl) induced oxidative stress in rats were determined by the generation of isoprostanoids. These are known to be robust biomarkers to evaluate nonenzymatic and free radical related oxidation. Other oxidative stress biomarkers such as hydroxyeicosatetraenoic acid products (HETEs) and cholesterol oxidation products (COPs) were also determined.

Phloroglucinol protects retinal pigment epithelium and photoreceptor against all-trans-retinal-induced toxicity and inhibits A2E formation.

Among retinal macular diseases, the juvenile recessive Stargardt disease and the age-related degenerative disease arise from carbonyl and oxidative stresses (COS). Both stresses originate from an accumulation of all-trans-retinal (atRAL) and are involved in bisretinoid formation by condensation of atRAL with phosphatidylethanolamine (carbonyl stress) in the photoreceptor and its transformation into lipofuscin bisretinoids (oxidative stress) in the retinal pigment epithelium (RPE). As atRAL and bisretinoid accumulation contribute to RPE and photoreceptor cell death, our goal is to select powerful chemical inhibitors of COS.

Omega-3 polyunsaturated lipophenols, how and why?

Polyphenols and n-3 polyunsaturated fatty acids (PUFAs) are two classes of natural compounds, which have been highlighted in epidemiological studies for their health benefits. The biological activities of those two families of metabolites on oxidation, inflammation, cancer, cardiovascular and degenerative diseases have been reported in vitro and in vivo. On the other hand, chemical bonding between the two structures leading to n-3 lipophenol derivatives (or phenolipids) has been studied in numerous works over the last decade, and some examples could also be found from natural sources.

Ligand efficiency driven design of new inhibitors of Mycobacterium tuberculosis transcriptional repressor EthR using fragment growing, merging, and linking approaches.

Tuberculosis remains a major cause of mortality and morbidity, killing each year more than one million people. Although the combined use of first line antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol) is efficient to treat most patients, the rapid emergence of multidrug resistant strains of Mycobacterium tuberculosis stresses the need for alternative therapies. Mycobacterial transcriptional repressor EthR is a key player in the control of second-line drugs bioactivation such as ethionamide and has been shown to impair the sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic.

Unconventional surface plasmon resonance signals reveal quantitative inhibition of transcriptional repressor EthR by synthetic ligands.

EthR is a mycobacterial repressor that limits the bioactivation of ethionamide, a commonly used anti-tuberculosis second-line drug. Several efforts have been deployed to identify EthR inhibitors abolishing the DNA-binding activity of the repressor. This led to the demonstration that stimulating the bioactivation of Eth through EthR inhibition could be an alternative way to fight Mycobacterium tuberculosis.

Tuberculosis: the drug development pipeline at a glance.

Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating.

Synthesis of 2',3'-dideoxynucleoside phosphoesters using H-phosphonate chemistry on soluble polymer support.

Phosphorylation of ddC and 3TC was efficiently performed on soluble poly(ethylene glycol) support. The corresponding 5'-monophosphate derivatives were obtained by oxidation of the support bound 5'-H-phosphonate intermediates. Then, di- and triphosphorylations were carried out using a carbonyldiimidazole activation step followed by nucleophilic substitution with suitable phosphate salts.

Insights into the soluble PEG-supported synthesis of cytosine-containing nucleoside 5'-mono-, di-, and triphosphates.

Nucleoside phosphoesters (nucleotides) have crucial roles in a large variety of biological processes including nucleic acid biosynthesis and their corresponding analogues are extensively used as biological tools. Herein, we describe a new and efficient synthetic procedure involving polyethylene glycol (PEG) as soluble support and regioselective mono-, di-, and triphosphorylation steps. Applied to natural and synthetic cytosine containing nucleosides, this methodology allowed the preparation of various phosphorylated forms in high yields and good purity.