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Mycobacterium tuberculosis AND drug use and [keywords]
- Mycobacterium Biofilms: Factors Involved in Development, Dispersal, and Therapeutic Strategies Against Biofilm-Relevant Pathogens. [JOURNAL ARTICLE]
- Crit Rev Eukaryot Gene Expr 2014; 24(3):269-279.
Many bacteria can develop biofilm (BF), a multicellular structure largely combining bacteria and their extracellular polymeric substances (EPS). The formation of biofilm results in an alternative existence in which microbes ensure their survival in adverse environments. Biofilm-relevant infections are more persistent, resistant to most antibiotics, and more recalcitrant to host immunity. Mycobacterium tuberculosis, the causative agent of tuberculosis, can develop biofilm, though whether M. tuberculosis can form biofilm within tuberculosis patients has yet to be determined. Here, we summarize the factors involved in the development and dispersal of mycobacterial biofilms, as well as underlying regulatory factors and inhibitors against biofilm to deepen our understanding of their development and to elucidate potential novel modes of action for future antibiotics. Key factors in biofilm formation identified as drug targets represent a novel and promising avenue for developing better antibiotics.
- Advanced immune suppression is associated with increased prevalence of mixed-strain Mycobacterium tuberculosis infections among persons at high risk for drug-resistant TB in Botswana. [JOURNAL ARTICLE]
- J Infect Dis 2014 Jul 28.
We examined factors associated with mixed Mycobacterium tuberculosis infections (MXTBI) among patients at high risk for drug-resistant tuberculosis in Botswana. Thirty-seven (10.0%) of 370 tuberculosis patients had MXTBI based on 24-locus MIRU-VNTR genotyping. In log-binomial regression analysis, age <37 years (adjusted prevalence ratio [aPR]=1.92; 95% confidence interval [CI]=1.01, 3.57) and prior TB treatment (aPR=2.31; 95% CI=1.09, 4.89) were associated with MXTBI. Among HIV-infected patients, prior TB treatment (aPR=2.11; 95% CI=1.04, 4.31) and CD4<100 cells/mL (aPR=10.18; 95% CI=2.48, 41.71) were associated with MXTBI. Clinical suspicion of mixed TB infections should be high for patients with advanced immunosuppression and prior TB treatment.
- Design, synthesis and antimycobacterial evaluation of 1-(4-(2-substitutedthiazol-4-yl)phenethyl)-4-(3-(4-substitutedpiperazin-1-yl)alkyl)piperazine hybrid analogues. [JOURNAL ARTICLE]
- Eur J Med Chem 2014 Jul 21.:605-613.
A series of twenty six new 1-(4-(2-substitutedthiazol-4-yl)phenethyl)-4-(3-(4-substitutedpiperazin-1-yl)alkyl)piperazine analogues were synthesized by seven steps and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Among the tested compounds, 7j, 7p, and 7r exhibited moderate activity (MIC = 6.25 μg/mL) and compounds 7a, 7f, 7g, 7n and 7v exhibited good activity (MIC = 3.125 μg/mL), while 7h displayed excellent activity (MIC = 1.56 μg/mL) by inhibiting 99% growth of M. tuberculosis H37Rv strain. In addition, all the active compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values for most of the compounds is >10 indicating suitability of compounds in an endeavour to attain lead molecule for further drug development.
- Metal Ions Effect on the Polarization of Metal Bound Water and Infrared Vibrational Modes of Coordinated Metal Center of Mycobacterium tuberculosis Pyrazinamidase via Quantum Mechanical Calculations. [JOURNAL ARTICLE]
- J Phys Chem B 2014 Jul 23.
Mycobacterium tuberculosis pyrazinamidase (PZAse) is a key enzyme to activate the pro-drug pyrazinamide (PZA). PZAse is a metalloenzyme that coordinates in vitro different divalent metal cofactors in a region called metal coordination site (MCS). Several metals including Co+2, Mn+2 and Zn+2 are able to reactivate the metal-depleted PZAse in vitro. We use quantum mechanical calculations to investigate the Zn+2, Fe+2 and Mn+2 metal cofactor effects on the local MCS structure, metal-ligands binding energy and charge distribution. Results suggest that the major metal-dependent changes occur in the metal-ligands binding energy and charge distribution. Zn+2 shows the highest binding energy to the ligands from protein. In addition, Zn+2 and Mn+2 within PZAse MCS highly polarize the O-H bond of coordinated water molecules in comparison with Fe+2. This suggests that the coordination of Zn+2 or Mn+2 to PZAse protein matrix facilitates the deprotonation of coordinated water to generate a nucleophile for catalysis as in carboxypeptidase A. Since metal ion binding is relevant to enzymatic reaction, identification of metal binding motif is important. The infrared vibrational mode shift of the C=Nε (His) bond from M. tuberculosis MCS is the best IR probe to metal complexation.
- Prevalence of gyrA and B gene mutations in fluoroquinolone-resistant and -sensitive clinical isolates of Mycobacterium tuberculosis and their relationship with MIC of ofloxacin. [JOURNAL ARTICLE]
- J Antibiot (Tokyo) 2014 Jul 23.
The study was done to know the prevalent mutations of gyrA and gyrB genes, and their significance with drug resistance in clinical isolates of Mycobacterium tuberculosis. A total of 100 ofloxacin- (OFX) resistant and 100 OFX-sensitive isolates of M. tuberculosis were consecutively selected from routine Tuberculosis laboratory. Drug resistance pattern of these isolates was recorded. MIC of OFX was tested in all these isolates by absolute concentration method. Quinolone resistance determining region (QRDR) of gyrA and gyrB genes of 320 and 428 bp, respectively, were amplified and sequenced. Sequencing data were analyzed by BLAST on NCBI with reference strain H37Rv. Of 100 OFX-sensitive isolates, 30 were pansusceptible, 28 were monoresistant, 10 were polyresistant and 32 were multidrug resistant (MDR). Among 100 OFX-resistant isolates, 19 were OFX monoresistant, 16 were polyresistant and 65 were MDR. Mutations in gyrA and gyrB genes were observed in 79% and 5% of OFX-resistant isolates, respectively. Most prevalent mutation was found at codon 94 in QRDR of gyrA gene. Double mutations found in gyrA gene and in both gyrA and gyrB genes signifies higher levels of OFX resistance. In one isolate, a substitution at codon 592 (Pro592Ser) was found as a novel mutation outside the QRDR of gyrB gene. Our findings support previous studies that the OFX resistance to M. tuberculosis is associated with mutations in the QRDR of gyrA gene; however, the level of OFX resistance may not be predicted based on the mutation patterns in the gyrA gene.The Journal of Antibiotics advance online publication, 23 July 2014; doi:10.1038/ja.2014.95.
- Molecular epidemiology of tuberculosis in Cambodian children. [JOURNAL ARTICLE]
- Epidemiol Infect 2014 Jul 22.:1-12.
SUMMARY We analysed Mycobacterium tuberculosis strains from children, hospitalized from January 2004 to July 2008 in the largest paediatric hospital complex in Cambodia. Specimens were tested for drug susceptibility and genotypes. From the 260 children, 161 strains were available. The East African-Indian genotype family was the most common (59·0%), increasing in frequency with distance from the Phnom Penh area, while the frequency of the Beijing genotype family strains decreased. The drug resistance pattern showed a similar geographical gradient: lowest in the northwest (4·6%), intermediate in the central (17·1%), and highest in the southeastern (30·8%) parts of the country. Three children (1·9%) had multidrug-resistant tuberculosis. The Beijing genotype and streptomycin resistance were significantly associated (P < 0·001). As tuberculosis in children reflects recent transmission patterns in the community, multidrug resistance levels inform about the current quality of the tuberculosis programme.
- Development of a Highly Biocompatible Antituberculosis Nanodelivery Formulation Based on Para-Aminosalicylic Acid-Zinc Layered Hydroxide Nanocomposites. [JOURNAL ARTICLE]
- ScientificWorldJournal 2014.:401460.
Tuberculosis is a lethal epidemic, difficult to control disease, claiming thousands of lives every year. We have developed a nanodelivery formulation based on para-aminosalicylic acid (PAS) and zinc layered hydroxide using zinc nitrate salt as a precursor. The developed formulation has a fourfold higher efficacy of PAS against mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) found to be at 1.40 μg/mL compared to the free drug PAS with a MIC of 5.0 μg/mL. The newly developed formulation was also found active against Gram-positive bacteria, Gram-negative bacteria, and Candida albicans. The formulation was also found to be biocompatible with human normal lung cells MRC-5 and mouse fibroblast cells-3T3. The in vitro release of PAS from the formulation was found to be sustained in a human body simulated phosphate buffer saline (PBS) solution at pH values of 7.4 and 4.8. Most importantly the nanocomposite prepared using zinc nitrate salt was advantageous in terms of yield and free from toxic zinc oxide contamination and had higher biocompatibility compared to one prepared using a zinc oxide precursor. In summary, these promising in vitro results are highly encouraging for the continued investigation of para-aminosalicylic acid and zinc layered hydroxide nanocomposites in vivo and eventual preclinical studies.
- The Inhibition of Folylpolyglutamate Synthetase (folC) in the Prevention of Drug Resistance in Mycobacterium tuberculosis by Traditional Chinese Medicine. [Journal Article]
- Biomed Res Int 2014.:635152.
Tuberculosis (TB) is an infectious disease caused by many strains of mycobacteria, but commonly Mycobacterium tuberculosis. As a possible method of reducing the drug resistance of M. tuberculosis, this research investigates the inhibition of Folylpolyglutamate synthetase, a protein transcript from the resistance association gene folC. After molecular docking to screen the traditional Chinese medicine (TCM) database, the candidate TCM compounds, with Folylpolyglutamate synthetase, were selected by molecular dynamics. The 10,000 ps simulation in association with RMSD analysis and total energy and structural variation defined the protein-ligand interaction. The selected TCM compounds Saussureamine C, methyl 3-O-feruloylquinate, and Labiatic acid have been found to inhibit the activity of bacteria and viruses and to regulate immunity. We also suggest the possible pathway in protein for each ligand. Compared with the control, similar interactions and structural variations indicate that these compounds might have an effect on Folylpolyglutamate synthetase. Finally, we suggest Saussureamine C is the best candidate compound as the complex has a high score, maintains its structural composition, and has a larger variation value than the control, thus inhibiting the drug resistance ability of Mycobacterium tuberculosis.
- A simple and rapid method to determine antimycobacterial potency of compounds using autoluminescent Mycobacterium tuberculosis. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Jul 21.
A major obstacle in the drug discovery process against Mycobacterium tuberculosis is its extremely slow growth rate and long generation time (∼20-24 h). Consequently, determination of Minimal Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of potential drug candidates, using current methods requires 7 days (resazurin based MIC Assay, REMA) and one month (CFU enumeration) respectively. We employed a synthetic luciferase operon optimized for expression in high-GC content bacteria and adapted it for use in mycobacteria. Using luminescence-based readouts we were able to determine the MIC and cidality of approved TB drugs, which correlated well with currently used methods. Luminescence-based readouts have been used previously to determine the MIC and cidality of approved TB drugs. Here, we adapted this assay to carry out a pilot screen using a library of 1114 compounds belonging to diverse chemical scaffolds and found that MICs derived from a 3-day luminescence assay matched well with REMA based MIC values. To determine bactericidal potency of compounds, a 1:10 dilution of the cultures from the MIC plate was carried out on day 7 and cidal concentrations determined based on time to positivity in 2 weeks, was found to be comparable with MBC values determined by the conventional CFU approach. Thus, the luminescent mycobacteria based approach is not only very simple and inexpensive but also allowed us to generate the information in half the time required by conventional methods.
- Pantothenic acid biosynthesis in the parasite Toxoplasma gondii: a target for chemotherapy. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Jul 21.
Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to Coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of inhibitions of growth of T. gondii. Two inhibitors exhibited lower effective concentrations than the current toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.