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In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics.

ABSTRACT: Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.

SUBMITTER: Bruhn DF

PROVIDER: S-EPMC4568539 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics.

Bruhn David F DF Scherman Michael S MS Liu Jiuyu J Scherbakov Dimitri D Meibohm Bernd B Böttger Erik C EC Lenaerts Anne J AJ Lee Richard E RE

Scientific reports 20150914

Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, ...[more]

PMID: 26365087

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Project description:Long duration of treatment, side-effects of currently used anti-tubercular drugs and emergence of drug-resistant forms of Mycobacterium tuberculosis (MTB) warrants the need to develop new drugs to tackle the scourge of tuberculosis (TB). Garlic is an edible plant reported to have anti-tubercular activity. However, previous researches on anti-tubercular effect of garlic were focused mostly on preliminary in vitro screening.To identify constituents responsible for anti-tubercular activity of thiosulfinate-derivative rich extract of garlic (GE) and to evaluate activity of the most active constituent in RAW 264.7 mouse macrophage cells infected with M. tuberculosis H37Rv (MTBH).In the present study, we have isolated eight compounds from GE by flash chromatography. The isolated compounds were characterized by 1H nuclear magnetic resonance spectroscopy, liquid chromatography-mass spectrometry and Fourier transform infrared spectroscopy. Individual isolates and GE were screened for activity against MTBH by Resazurin Microtitre Plate Assay (REMA).Anti-tubercular activity of GE was superior to that of isolates when evaluated by REMA, possibly due to synergism amongst the constituents of GE. Cytotoxicity of GE was evaluated in RAW 264.7 mouse macrophage cells and it was observed that GE had a favorable selectivity index (>10). Therefore, anti-tubercular activity of GE was further evaluated by intracellular macrophage infection model. GE demonstrated concentration-dependent activity in macrophages infected with MTBH.This is the first report on intracellular anti-tubercular activity of any extract of garlic or its components. Appreciable intracellular anti-tubercular activity of GE in macrophages combined with low cytotoxicity makes it a suitable candidate for further development as an anti-tubercular agent.Thiosulfinate-derivative rich extract of Allium sativum showed better activity than its isolated constituents against Mycobacterium tuberculosis H37Rv.(MTBH) when evaluated by Resazurin Microtitre Plate AssayThe extract showed least cytotoxic potential against RAW 264.7 mouse macrophage cells as compared to rifampicin, isoniazid and ethambutol when evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The extract had an appreciable selectivity indexExtract showed appreciable activity in RAW 264.7 mouse macrophage cells infected with MTBH, indicating its potential to be developed further as an anti-tubercular agent that can be administered as an adjunct to the existing anti-tubercular drug regimen. Abbreviations used: TB: Tuberculosis, MTB: Mycobacterium tuberculosis, MTBH: Mycobacterium tuberculosis H37Rv, GE: Thiosulfinate-derivative rich extract of garlic, REMA: Resazurin Microtitre Plate Assay, VD: Vinyldithiin, CFU: Colony forming unit, 1H NMR: 1H nuclear magnetic resonance spectroscopy, FT-IR: Fourier transform-infrared spectroscopy, LC-MS: Liquid chromatography-mass spectrometry, IC50: Concentration required to inhibit the cells by 50%, ANOVA: Analysis of variance.

Project description:BackgroundAccurate evaluation of anti-tubercular therapy (ATT) responses is crucial for both diagnosis and treatment of intestinal tuberculosis (ITB). Little is known about the role of cross-sectional imaging techniques in ITB follow-up assessment. We aimed to investigate the accuracy of cross-sectional imaging modalities, CT enterography (CTE) and gastrointestinal ultrasound (GIUS), in the evaluation of ATT responses in ITB patients.MethodsPatients diagnosed with ITB and followed up by CTE and/or GIUS were retrospectively searched in the databases. Clinical, imaging, laboratory and endoscopic data were collected at baseline and the first follow-up visit. Responses were graded as good, partial and no response based on protocols described in the literature and by our institution. CTE evaluation was based on changes in the lesion area, mural thickness, enhancement patterns and lymph nodes, while GIUS evaluation was based on changes in bowel wall morphology and the Limberg score. Clinical evaluation was used as the gold-standard evaluation method, which was determined by a comprehensive impression of endoscopic changes along with symptomatic improvement and laboratory tests, with imaging results masked.ResultsTwenty patients with ITB were enrolled in our study. The first follow-up time was from 2 to 12 months (average 6 months). According to the gold standard evaluation, 11 patients were evaluated as having a good ATT response, while 9 had a partial response. A total of 18 patients were followed up by CTE, while 7 were followed up by GIUS, depending on medical and/or financial considerations. The accuracy of CTE and GIUS was 83% (15/18) and 85.7% (6/7), respectively. The sensitivity, specificity, PPV and NPV of CTE were 88.9, 77.8, 80 and 87.5%, respectively. Moreover, the sensitivity, specificity, PPV and NPV of GIUS were 100, 50, 83.3 and 100%, respectively. By combining the results of CTE and GIUS results, the overall accuracy was 90%, with sensitivity and specificity of 91.7 and 87.5%, respectively.ConclusionTo our knowledge, this is the first study exploring the accuracy of the cross-sectional imaging modalities CTE/GIUS in the evaluation of ATT responses. Our results indicated their promising application prospect in clinical practice as a non-invasive and cost-effective approach.

Dataset Information

In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics.

Publications

In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics.

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