Pyrazinamide is active against Mycobacterium tuberculosis at neutral pH at the clinical breakpoint concentration under specific conditions

2016 ◽  
Author(s):  
Alice den Hertog
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Neutral Ph

scholarly journals The Combination Rifampin-Nitazoxanide, but Not Rifampin-Isoniazid-Pyrazinamide-Ethambutol, Kills DormantMycobacterium tuberculosisin Hypoxia at Neutral pH

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Angelo Iacobino ◽  
Federico Giannoni ◽  
Manuela Pardini ◽  
Giovanni Piccaro ◽  
Lanfranco Fattorini
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Content Type ◽  
Neutral Ph ◽  
Dormant Cells ◽  
Human Therapy

ABSTRACTThe activities of rifampin, nitazoxanide, PA-824, and sutezolid were tested against dormantMycobacterium tuberculosisunder conditions mimicking caseous granulomas (hypoxia at pH 7.3) in comparison with those of the combination rifampin-isoniazid-pyrazinamide-ethambutol (R-I-Z-E), which is used for human therapy. Mycobacterial viability was monitored by CFU and regrowth in MGIT 960. As shown by lack of regrowth in MGIT, rifampin-nitazoxanide-containing combinations, but not R-I-Z-E, killed dormant cells in 28 to 35 days. These observations might be important in designing new tuberculosis therapies.

scholarly journals Pyrazinamide Is Active against Mycobacterium tuberculosis Cultures at Neutral pH and Low Temperature

2016 ◽  
Vol 60 (8) ◽  
pp. 4956-4960 ◽  
Author(s):  
Alice L. den Hertog ◽  
Sandra Menting ◽  
Richard Pfeltz ◽  
Matthew Warns ◽  
Salman H. Siddiqi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Low Temperature ◽  
Susceptibility Testing ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Acidic Ph ◽  
Content Type ◽  
The Past ◽  
Neutral Ph

ABSTRACTFor the past decades, an acidic pH has been used to renderMycobacterium tuberculosissusceptible to pyrazinamide forin vitrotesting. Here, we show that at the standard breakpoint concentration and reduced culture temperatures, pyrazinamide (PZA) is active against tuberculosis (TB) at neutral pH. This finding should help unravel the mechanism of action of PZA and allow drug susceptibility testing (DST) methods to be optimized.

scholarly journals Mycobacterium tuberculosis Is Selectively Killed by Rifampin and Rifapentine in Hypoxia at Neutral pH

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Angelo Iacobino ◽  
Giovanni Piccaro ◽  
Federico Giannoni ◽  
Alessandro Mustazzolu ◽  
Lanfranco Fattorini
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Content Type ◽  
Neutral Ph

ABSTRACT The activities of rifampin, rifapentine, bedaquiline, PA-824, clofazimine, nitazoxanide, isoniazid, amikacin, moxifloxacin, niclosamide, thioridazine, and pyrazinamide were tested against nonreplicating (dormant) Mycobacterium tuberculosis H37Rv under conditions of hypoxia at pHs 5.8 and 7.3, mimicking environments of cellular granulomas and caseous granulomas, respectively. At pH 5.8, several drugs killed dormant bacilli, with the best being rifampin and rifapentine. At pH 7.3, only rifampin and rifapentine efficiently killed dormant bacilli, while all other drugs showed little activity.

scholarly journals Activity of Pyrazinamide against Mycobacterium tuberculosis at Neutral pH in PZA-S1 Minimal Medium

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 909
Author(s):  
Wanliang Shi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimal Medium ◽  
Susceptibility Testing ◽  
Agar Plate ◽  
Diffusion Method ◽  
Acidic Ph ◽  
Disk Diffusion Method ◽  
Neutral Ph ◽  
Broth Microdilution Method ◽  
Minimal Media

Susceptibility testing of tuberculosis (TB) drugs on Mycobacterium tuberculosis is essential for the rapid detection of strains resistant to the drugs, providing the patient with effective treatment, and preventing the spread of drug-resistant TB strains. Pyrazinamide (PZA) is one of the first-line agents used for the treatment of TB. However, current phenotypic PZA susceptibility testing is unreliable due to its performance in acidic pH conditions. The aims of this study were to develop minimal media to determine the activity of PZA at a neutral pH at 37 °C to avoid problems caused by an acidic pH, which is currently used in PZA susceptibility tests, and to identify PZA-resistant M. tuberculosis in media with reproducibility and accuracy. Different minimal media were used to determine the activity of PZA using the broth microdilution method with M. tuberculosis H37Ra as the reference strain. The PZA-S1 minimal medium was proposed as the most suitable medium. PZA inhibited the growth of M. tuberculosis in PZA-S1 at a neutral pH of 6.8, which is the optimal pH for M. tuberculosis growth. Moreover, PZA showed activity at a neutral pH on a PZA-S1 agar plate when using the disk diffusion method. PZA-resistant M. tuberculosis could be identified at a neutral pH in PZA-S1 minimal medium. This study establishes valuable information regarding the testing of PZA’s susceptibility in relation to M. tuberculosis at a neutral pH of 6.8 with reliability and accuracy in clinical settings.

scholarly journals AC2P20 selectively kills Mycobacterium tuberculosis at acidic pH by depleting free thiols

RSC Advances ◽  
2021 ◽  
Vol 11 (33) ◽  
pp. 20089-20100
Author(s):  
Shelby J. Dechow ◽  
Garry B. Coulson ◽  
Michael W. Wilson ◽  
Scott D. Larsen ◽  
Robert B. Abramovitch
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Redox Homeostasis ◽  
Acidic Ph ◽  
Chemical Probe ◽  
Neutral Ph ◽  
Thiol Redox

Mycobacterium tuberculosis (Mtb) is killed by the chemical probe AC2P20 at acidic pH, but not neutral pH. AC2P20 depletes Mtb free thiols at acidic pH showing Mtb is selectively sensitive to agents targeting thiol-redox homeostasis at acidic pH.

scholarly journals Membrane Insertion of Mycobacterium tuberculosis EsxA in Cultured Lung Epithelial Cells

2020 ◽  
Author(s):  
Qi Zhang ◽  
Javier Aguilera ◽  
Salvador Vazquez Reyes ◽  
Jianjun Sun
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Epithelial Cells ◽  
Cytolytic Activity ◽  
Current Data ◽  
Lung Epithelial Cells ◽  
Neutral Ph ◽  
Subcellular Compartments ◽  
Lung Epithelial ◽  
Important Virulence Factor ◽  
First Time

AbstractEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb cytosolic translocation presumably by penetrating phagosomal membranes with its acidic pH-dependent membrane permeabilizing activity (MPA). However, current data suggest that the observed cytolytic activity of EsxA at neutral pH is due to contamination of ASB-14, a detergent used in EsxA protein purification, and the role of EsxA MPA in Mtb cytosolic translocation is also questionable. Here, we have obtained evidence that it is ASB-14, not EsxA that causes cytolysis at neutral pH. Quantitative liquid chromatography and mass spectrometry showed that even after gel filtration, dialysis, or passing through detergent removal column, the remaining ASB-14 in the EsxA protein solution was still at a concentration enough to kill cultured lung epithelial cells. When treated with trypsin or proteinase K, the digested EsxA protein solution with ASB-14 was still cytotoxic. Interestingly, however, we have found that the exogenously added EsxA is endocytosed into lung epithelial cells and inserts into the host membranes within acidic subcellular compartments, which can be blocked by cytochalasin D and bafilomycin A. It is for the first time EsxA is found to insert into the host membranes within acidic subcellular compartments.ImportanceEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb virulence. However, current data regarding to its role in Mtb virulence are controversial. Here, we have obtained evidence showing that the cytolytic activity of EsxA at neutral pH is due to contamination of ASB-14, a detergent used in EsxA preparation. Moreover, it is for the first time we have found that EsxA protein is endocytosed into lung epithelial cells and inserts into the host membranes within acidic subcellular compartments, implicating an important role of the acidic pH-dependent membrane permeabilizing activity of EsxA in Mtb virulence.

Examination of Rabbit Fc Crystals

1968 ◽  
Vol 26 ◽  
pp. 140-141
Author(s):  
J. P. Robinson ◽  
P. G. Lenhert
Keyword(s):  
Molecular Weight ◽  
Flat Plate ◽  
Phosphate Buffer ◽  
Asymmetric Unit ◽  
X Ray Diffraction ◽  
X Ray ◽  
Neutral Ph ◽  
Small Crystals ◽  
Carbon Coated ◽  
Diffraction Patterns

Crystallographic studies of rabbit Fc using X-ray diffraction patterns were recently reported. The unit cell constants were reported to be a = 69. 2 A°, b = 73. 1 A°, c = 60. 6 A°, B = 104° 30', space group P21, monoclinic, volume of asymmetric unit V = 148, 000 A°3. The molecular weight of the fragment was determined to be 55, 000 ± 2000 which is in agreement with earlier determinations by other methods.Fc crystals were formed in water or dilute phosphate buffer at neutral pH. The resulting crystal was a flat plate as previously described. Preparations of small crystals were negatively stained by mixing the suspension with equal volumes of 2% silicotungstate at neutral pH. A drop of the mixture was placed on a carbon coated grid and allowed to stand for a few minutes. The excess liquid was removed and the grid was immediately put in the microscope.

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