Changing white into brite adipocytes. Focus on >BMP4 and BMP7 induce the white-to-brown transition of primary human adipose stem cells>

Editorial.This review was supported by Grants S2010/BMD-2423 from Comunidad de Madrid and SAF2012-32491 from MINECO (Ministerio de Economia y Competitividad), Spain (to M.-J. Obregon).Peer Reviewe

Design, synthesis and biological evaluation of 2-nitroimidazopyrazin-one/-es with antitubercular and antiparasitic activity

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that anti-tubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazo-oxazines. Synthetic analogs with the novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed, synthesized and structure activity relationships generated. Selected derivatives had potent antiparasitic and antitubercular activity whilst maintaining drug-like properties such as low cytotoxicity against mammalian cell lines (CC50 >100 μM), good metabolic stability in human and mouse liver microsomes and high apparent permeability in a Caco-2 model of intestinal absorption. The kinetic solubility of the new bicyclic derivatives varied, and was found to be a key parameter for future optimization. Taken together, these results suggest promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development

Firefly Bioluminescence-Based Detection of ATP

Adenosine triphosphate (ATP) bioluminescence is a powerful light-producing phenomenon that occurs in nature in a variety of organisms, with ATP bioluminescence of fireflies one of the most well-known examples. The firefly ATP bioluminescence reaction has been adapted to the laboratory with a wide range of applications that include monitoring cellular processes, antimicrobial susceptibility testing, and the detection of bacterial contamination of environmental surfaces. ATP bioluminescence occurs through a multistep reaction between firefly luciferase, ATP, magnesium salt, and oxygen (Scheme 1).[1] As a simplified overview, luciferyl adenylate 2 is first formed from luciferin 1 and Mg2+-ATP. The luciferyl adenylate 2 is then oxidised with molecular oxygen to form a dioxetanone cyclic peroxide intermediate 3. Following intramolecular conversion to produce electronically excited states of oxyluciferin, the dioxetanone is decarboxylated. Finally, the return of excited oxyluciferin to the ground state 5 results in emission of visible light. For more detailed insights into the reaction mechanism, including alternative reactions and different tautomers of oxyluciferin at varying pH values, readers are referred to additional literature

The eagle effect and antibiotic-induced persistence: two sides of the same coin?

The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports

Nitroimidazoles: Molecular fireworks that combat a broad spectrum of infectious diseases

Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted

Clostridium difficile drug pipeline: challenges in discover and development of new agents

In the past decade Clostridium difficile has become a bacterial pathogen of global significance. Epidemic strains have spread throughout hospitals, while community acquired infections and other sources ensure a constant inoculation of spores into hospitals. In response to the increasing medical burden, a new C. difficile antibiotic, fidaxomicin, was approved in 2011 for the treatment of C. difficile-associated diarrhea. Rudimentary fecal transplants are also being trialed as effective treatments. Despite these advances, therapies that are more effective against C. difficile spores and less damaging to the resident gastrointestinal microbiome and that reduce recurrent disease are still desperately needed. However, bringing a new treatment for C. difficile infection to market involves particular challenges. This review covers the current drug discovery pipeline, including both small molecule and biologic therapies, and highlights the challenges associated with in vitro and in vivo models of C. difficile infection for drug screening and lead optimization

Detection and Investigation of Eagle Effect Resistance to Vancomycin in With an ATP-Bioluminescence Assay.

Vancomycin was bactericidal against Clostridium difficile at eightfold the minimum inhibitory concentration (MIC) using a traditional minimum bactericidal concentration (MBC) assay. However, at higher concentrations up to 64 × MIC, vancomycin displayed a paradoxical “more-drug-kills-less” Eagle effect against C. difficile. To overcome challenges associated with performing the labor-intensive agar-based MBC method under anaerobic growth conditions, we investigated an alternative more convenient ATP-bioluminescence assay to assess the Eagle effect in C. difficile. The commercial BacTiter-GloTM assay is a homogenous method to determine bacterial viability based on quantification of bacterial ATP as a marker for metabolic activity. The ATP-bioluminescence assay was advantageous over the traditional MBC-type assay in detecting the Eagle effect because it reduced assay time and was simple to perform; measurement of viability could be performed in less than 10 min outside of the anaerobic chamber. Using this method, we found C. difficile survived clinically relevant, high concentrations of vancomycin (up to 2048 μg/mL). In contrast, C. difficile did not survive high concentrations of metronidazole or fidaxomicin. The Eagle effect was also detected for telavancin, but not for teicoplanin, dalbavancin, oritavancin, or ramoplanin. All four pathogenic strains of C. difficile tested consistently displayed Eagle effect resistance to vancomycin, but not metronidazole or fidaxomicin. These results suggest that Eagle effect resistance to vancomycin in C. difficile could be more prevalent than previously appreciated, with potential clinical implications. The ATP-Bioluminescence assay can thus be used as an alternative to the agar-based MBC assay to characterize the Eagle effect against a variety of antibiotics, at a wide-range of concentrations, with much greater throughput. This may facilitate improved understanding of Eagle effect resistance and promote further research to understand potential clinical relevance