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Antimicrobial resistance (AMR) is one of the most important global public health problems. The imprudent use of antibiotics in humans and animals has resulted in the emergence of antibiotic-resistant bacteria. The dissemination of these strains and their resistant determinants could endanger antibiotic efficacy. Therefore, there is an urgent need to identify and develop novel strategies to combat antibiotic resistance. This review provides insights into the evolution and the mechanisms of AMR. Additionally, it discusses alternative approaches that might be used to control AMR, including probiotics, prebiotics, antimicrobial peptides, small molecules, organic acids, essential oils, bacteriophage, fecal transplants, and nanoparticles. [ABSTRACT FROM AUTHOR]

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro‐apoptotic lipid catabolized by ceramidase enzymes to produce pro‐proliferative sphingosine‐1‐phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug‐like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to revealing a new paradigm for inhibition of lipid metabolising enzymes with non‐lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts. [ABSTRACT FROM AUTHOR]

The equilibrium between the pro-apoptotic ceramide and pro-vital sphingosine-1-phosphate is considered to be decisive for cell death or survival. The different ceramidases thus play key roles in cell fate and might offer attractive targets for pharmacological intervention. Although until recently only moderately active inhibitors have been described, first in vivo experiments suggest activity against cancer cell survival and multi-drug resistance. Here, we provide a brief overview on the different ceramidases, and we will review the known inhibitors and current strategies for further inhibitor development. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

[Display omitted] • Small molecule selective ceramidase inhibitors. • Dietary ceramide suppresses colorectal cancer. Ceramides impact a diverse array of biological functions and have been implicated in disease pathogenesis. The enzyme neutral ceramidase (nCDase) is a zinc-containing hydrolase and mediates the metabolism of ceramide to sphingosine (Sph), both in cells and in the intestinal lumen. nCDase inhibitors based on substrate mimetics, for example C6-urea ceramide, have limited potency, aqueous solubility, and micelle-free fraction. To identify non-ceramide mimetic nCDase inhibitors, hit compounds from an HTS campaign were evaluated in biochemical, cell based and in silico modeling approaches. A majority of small molecule nCDase inhibitors contained pharmacophores capable of zinc interaction but retained specificity for nCDase over zinc-containing acid and alkaline ceramidases, as well as matrix metalloprotease-3 and histone deacetylase-1. nCDase inhibitors were refined by SAR, were shown to be substrate competitive and were active in cellular assays. nCDase inhibitor compounds were modeled by in silico DOCK screening and by molecular simulation. Modeling data supports zinc interaction and a similar compound binding pose with ceramide. nCDase inhibitors were identified with notably improved activity and solubility in comparison with the reference lipid-mimetic C6-urea ceramide. [ABSTRACT FROM AUTHOR]