Dataset Information

Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis.

ABSTRACT: Eleven fatty acid analogues incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit the growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogues displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb, with MIC values equal to or below those observed with the anti-tuberculosis drugs D-cycloserine and isoniazid. In contrast, two of the analogues that display the greatest activity against Mtb failed to inhibit E.?coli growth under either set of conditions. Thus, the active molecules identified herein may provide the basis for the development of anti-mycobacterial agents against Mtb.

SUBMITTER: Sittiwong W

PROVIDER: S-EPMC4142477 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis.

Sittiwong Wantanee W Zinniel Denise K DK Fenton Robert J RJ Marshall Darrell D DD Story Courtney B CB Kim Bohkyung B Lee Ji-Young JY Powers Robert R Barletta Raúl G RG Dussault Patrick H PH

ChemMedChem 20140605 8

Eleven fatty acid analogues incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit the growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogues displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb, with MIC values equal to or below those observed with th ...[more]

PMID: 24902951

Similar Datasets

Project description:Human hepatoma HepG2 cells (American Type Culture Collection; HB-8065) were grown in 75 ml tissue cell culture flasks in Eagle's minimal essential medium (EMEM) augmented with 10% fetal bovine serum at 37°C in a humidified atmosphere with 5% CO2. For treatment with fatty acids or analogues, the cells were seeded at a density of 2 × 106 cells in a T25-cm2 flask for 24 h. Each FA or analogue was added to the culture medium as a fatty acid-bovine serum albumin (BSA) complex (2.5:1, FA:BSA) to give the desired final concentration. The controls in these experiments were HepG2 cells with BSA alone. After 24 h treatment, the media was collected, cells were rinsed twice with PBS and cells were harvested for analysis. To each cell suspension prior to lipid extraction a standard mixture of 25 µg C15:0 PE, C17:0 PC and C71:1 TAG was added as standards. Extraction of lipids was performed according to the Folch method. For metabolomics analysis, the lipid extracts were resuspended in chloroform/methanol, 2:1 (v/v).All analyses were carried out using an Agilent 1200 Series HPLC, ACE 5 C8-300 column (2.1 x 100 mm) and linear gradient elution at a flow rate of 0.1 mL/min. Mobile phase A and B consisted of 0.1% formic acid; 10 mM ammonium acetate in H2O and 0.1% formic acid; 10 mM ammonium acetate in ACN/isopropanol (50/50; v/v), respectively. The injection volume was 4 µL. Separation of metabolites was achieved at the following gradient: T=0 min: 30% B; T=1 min: 30% B; T=25 min: 100% B; T=45 min: 100% B; T=47 min: 30% B; and T=60 min: 30% B (re-equilibration). The HPLC system was directly coupled to a Bruker Soalrix 70 Hybrid FTMS instrument equipped with electrospray ionization source (ESI) (Bruker Daltonics). The system was controlled by HyStar v.3.4.8.0 software. MS data was collected with resolving power of 78,000 (at m/z 400) in positive or negative mode under following conditions: a capillary voltage of (+/-) 4,500 V and an end plate offset of -500 V. The dry temperature was set at 180°C. Dry gas flow was maintained 4 L/min. Acquisition range was 244-1,800 m/z with 0.2 s ion accumulation time. LC-MS data was converted into mzXML format using CompassXport v. 3.0.6 and processed by mzMine v.2.10 [25] or XCMS data analysis software. Data processing involved mass detection, chromatographic peak detection and deconvolution, isotopic peaks grouping, normalization and peak alignment. Metabolite data were mean-centered and unit-variance scaled to remove the offsets and adjust the importance of high and low abundance metabolites to an equal level. Significantly altered metabolites were defined by a fold change (FC) >2 and p<0.05. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) of signature metabolites altered in compounds treated cells compared to control were performed in the Metaboanalyst web portal (www.metaboanalyst.ca).

Project description:BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. METHODS:Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. FINDINGS:CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, ?SMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. INTERPRETATION:OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.

Dataset Information

Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis.

Publications

Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets