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Mycobacterium tuberculosis AND drug use and [keywords]
- A novel peptide interferes with Mycobacterium tuberculosis virulence and survival. [Journal Article]
- FEBS Open Bio 2014.:735-40.
Tuberculosis (TB) is a huge global burden, with new and resistant strains emerging at an alarming rate, necessitating an urgent need for a new class of drug candidates. Here, we report that SL3, a novel 33-amino acid peptide, causes debilitating effects on mycobacterial morphology. Treatment with SL3 drastically inhibits the growth of Mycobacterium tuberculosis in vitro as well as in a pre-clinical mouse model for M.tb infection. Microarray analysis of SL3-expressing strain demonstrates wide-scale transcriptional disruption in M.tb. We therefore believe that SL3 and similar peptides may herald a new approach towards discovering new molecules for TB therapy.
- Antimycobacterial Efficacy of Andrographis paniculata Leaf Extracts Under Intracellular and Hypoxic Conditions. [JOURNAL ARTICLE]
- J Evid Based Complementary Altern Med 2014 Oct 26.
The inhibition of the growth of Mycobacterium tuberculosis by the extracts of Andrographis paniculata has been studied using intracellular and axenic hypoxic conditions. The inhibition (confirmed using the gold standard colony forming unit assay) was found to increase with "double stimuli" or higher concentration of the extract. Organic solvent extracts were found to inhibit bacterial growth more than the aqueous extracts under microaerophilic conditions mimicked through axenic and intracellular assays. This could be further explored to evaluate the potential of the plant to be used against nonreplicating/dormant bacilli.
- Roles of Ala-149 in the catalytic activity of diadenosine tetraphosphate phosphorylase from Mycobacterium tuberculosis H37Rv. [JOURNAL ARTICLE]
- Biosci Biotechnol Biochem 2014 Oct 28.:1-3.
Diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap4A) phosphorylase from Mycobacterium tuberculosis H37Rv (MtAPA) belongs to the histidine triad motif (HIT) superfamily, but is the only member with an alanine residue at position 149 (Ala-149). Enzymatic analysis revealed that the Ala-149 deletion mutant displayed substrate specificity for diadenosine 5',5'''-P(1),P(5)-pentaphosphate and was inactive on Ap4A and other substrates that are utilized by the wild-type enzyme.
- [Quantitative proteomics analysis of ClpS-mediated rifampicin resistance in Mycobacterium]. [English Abstract, Journal Article, Research Support, Non-U.S. Gov't]
- Sheng Wu Gong Cheng Xue Bao 2014 Jul; 30(7):1115-27.
Adaptor protein ClpS is an essential regulator of prokaryotic ATP-dependent protease ClpAP, which delivers certain protein substrates with specific amino acid sequences to ClpAP for degradation. However, ClpS also functions as the inhibitor of the ClpAP-mediated protein degradation for other proteins. Here, we constructed the clpS-overexpression Mycobacterium smegmatis strain, and showed for the first time that overexpression of ClpS increased the resistance of M. smegmatis to rifampicin that is one of most widely used antibiotic drugs in treatment of tuberculosis. Using quantitative proteomic technology, we systematically analyzed effects of ClpS overexpression on changes in M. smegmatis proteome, and proposed that the increased rifampicin resistance was caused by ClpS-regulated drug sedimentation and drug metabolism. Our results indicate that the changes in degradation related proteins enhanced drug resistance and quantitative proteomic analysis is an important tool for understanding molecular mechanisms responsible for bacteria drug resistance.
- [Preface for special issue on proteomics (2014)]. [English Abstract, Introductory Journal Article]
- Sheng Wu Gong Cheng Xue Bao 2014 Jul; 30(7):1001-3.
Proteomics is one of the most important functional genomics research in the post-genomic era, which is closely related to medical biology, chemistry, physics, information science and modern technology. Through review research progress of some important proteomics, a proteomics special issue is published so as to find problems, explore the possible applications and outlook the development prospects of proteomics. The special issue consists of reviews and original papers, mainly involving in the following aspects, i) proteomics about different species such as humans, mammals, prokaryotes and actinobacterial; ii) proteomics methodology and techniques including tandem mass spectrometry analysis, film (urimem) preservation of urine protein, quantitative proteomic analysis and meta analysis; iii) function and application of proteome such as spider (Latrodectus tredecimguttatus) toxins proteome, protein phosphorylation proteome, oocytes and early embryos proteomes, liver fibrosis proteome, drug-resistant mycobacterium tuberculosis proteome, etc.
- Automated liquid culture system misses isoniazid heteroresistance in Mycobacterium tuberculosis isolates with mutations in the promoter region of the inhA gene. [JOURNAL ARTICLE]
- Eur J Clin Microbiol Infect Dis 2014 Oct 26.
Heteroresistance in Mycobacterium tuberculosis isolates remains the major challenge for phenotypic drug susceptibility testing (DST) methods to detect drug resistance. The aim of this study was to investigate the abilities of phenotypic DST methods to identify the isoniazid (INH) heteroresistance in M. tuberculosis. We found that the broth dilution method was able to detect INH resistance if 0.5 % resistant bacteria with mutations in the katG and oxyR-ahpC regions were present, while the detection limit ranged from 1 to 10 % for the INH-resistant strains harboring inhA mutations, which was associated with the different mutant types. Additionally, MGIT DST was able to find the recommended 1 % INH resistance due to katG mutations. In contrast, MGIT DST detected resistance in suspensions with 20 % resistant bacteria with inhA mutations. Statistical analysis revealed that the ability of the broth dilution method to detect heteroresistance was better than that of the MGIT DST (p = 0.004). When we further pairwise compared the two methods for detecting heteroresistance according to different mutant loci, the broth dilution method found more heteroresistance due to inhA mutations than MGIT DST (p = 0.001), while the differences for katG and oxyR-ahpC mutations were both not statistically significant (p > 0.05). In conclusion, our findings demonstrate that MGIT DST fails to detect INH heteroresistance in M. tuberculosis isolates with mutations in the promoter region of inhA. In addition, the broth dilution method is more sensitive than MGIT DST in finding INH heteroresistance, indicating that this method may serve as an alternative method to detect the heteroresistance of M. tuberculosis.
- Time-kill kinetics of antibiotics active against rapidly growing mycobacteria. [JOURNAL ARTICLE]
- J Antimicrob Chemother 2014 Oct 25.
This study was conducted to generate basic pharmacodynamic information on the relationship between antibiotic concentrations and the growth of rapidly growing mycobacteria (RGM), and thereby contribute to a better understanding of current and future drug regimens for diseases caused by RGM.Type strains of Mycobacterium abscessus and Mycobacterium fortuitum were used; the MICs of cefoxitin, amikacin, moxifloxacin, linezolid and clarithromycin were determined by broth microdilution. Time-kill assays were performed, exposing the bacteria to 2-fold concentrations from 0.25 to 32 times the MIC at 30°C for 120 h. The sigmoid maximum effect (Emax) model was fitted to the time-kill curves data.The highest killing of M. abscessus was observed between 24 and 72 h; amikacin had the highest Emax (0.0427 h(-1)), followed by clarithromycin (0.0231 h(-1)) and cefoxitin (0.0142 h(-1)). For M. fortuitum, between 3 and 24 h, amikacin also showed the highest Emax (0.1933 h(-1)). There were no significant differences between the Hill's slopes determined for all the antibiotics tested against M. abscessus or M. fortuitum (P = 0.2213 and P = 0.2696, respectively).The total effect observed for all antibiotics was low and primarily determined by the Emax and not by the Hill's slope. The limited activity detected fits well with the poor outcome of antibiotic treatment for disease caused by RGM, particularly for M. abscessus. An evaluation of drug combinations will be the next step in understanding and improving current treatment standards.
- Medical devices; immunology and microbiology devices; classification of nucleic acid-based devices for the detection of Mycobacterium tuberculosis complex and the genetic mutations associated with antibiotic resistance. Final order. [Journal Article]
- Fed Regist 2014 Oct 22; 79(204):63034-6.
The Food and Drug Administration (FDA) is classifying nucleic acid-based in vitro diagnostic devices for the detection of Mycobacterium tuberculosis complex (MTB-complex) and the genetic mutations associated with MTB-complex antibiotic resistance in respiratory specimens devices into class II (special controls). The Agency is classifying the device into class II (special controls) because special controls, in addition to general controls, will provide a reasonable assurance of safety and effectiveness of the device.
- Genotypic susceptibility testing of Mycobacterium tuberculosis for Amikacin and Kanamycin resistance using a rapid Sloppy Molecular Beacon based assay identifies more cases of low level drug resistance than phenotypic Lowenstein-Jensen testing. [JOURNAL ARTICLE]
- J Clin Microbiol 2014 Oct 22.
Resistance to Amikacin (AMK) and Kanamycin (KAN) in clinical Mycobacterium tuberculosis (M.tb) strains is largely determined by specific mutations in the rrs gene and eis gene promoter. We developed a rapid, multiplexed Sloppy Molecular Beacon (SMB) assay to identify these mutations and then evaluated assay performance on 603 clinical M.tb DNA samples collected in South Korea. Assay performance was compared to gold-standard phenotypic drug susceptibility tests including Lowenstein-Jensen (LJ) absolute concentration, Mycobacterial Growth Indicator Tubes (MGIT) and TREK Sensititre® MYCOTB MIC plate (MYCOTB) methods. Target amplicons were also tested for mutations by Sanger sequencing. The SMB assay correctly detected 115/116 mutant and mixed sequences and 487/487 wild type sequences (sensitivity and specificity 99.1 and 100% respectively). Using LJ as the reference, sensitivity and specificity for AMK resistance was 92.2% and 100% respectively; and for KAN resistance was 87.7% and 95.6% respectively. Mutations in the rrs gene were unequivocally associated with high level cross-resistance to AMK and KAN in all three conventional drug susceptibility testing methods. However, eis promoter mutations were associated with KAN resistance using only the MGIT or MYCOTB methods but not the LJ method. No testing method associated eis promoter mutations with AMK resistance. Among the discordant samples with AMK and/or KAN resistance but wild type sequence at the target genes, we discovered four new mutations in the whiB7 5' untranslated (UTR) region in 6/22 samples. All the six samples were resistant to only KAN suggesting the possible role of these whiB7 5' UTR mutations in KAN resistance.
- Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide. [Journal Article]
- Int J Nanomedicine 2014.:4749-62.
The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB.