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Chopra S.,SRI International | Matsuyama K.,SRI International | Tran T.,SRI International | Malerich J.P.,SRI International | And 9 more authors.
Journal of Antimicrobial Chemotherapy

Objectives: New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance to existing agents and shorten the duration of therapy. Targeting DNA gyrase is a clinically validated therapeutic approach using fluoroquinolone antibiotics to target the gyrase subunit A (GyrA) of the heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting the gyrase subunit B (GyrB), which has not been targeted for TB. The biological activities of two potent small-molecule inhibitors of GyrB have been characterized to validate its targeting as a therapeutic strategy for treating TB. Materials and methods: Novobiocin and aminobenzimidazole 1 (AB-1) were tested for their activity against Mycobacterium tuberculosis (Mtb) H37Rv and other mycobacteria. AB-1 and novobiocin were also evaluated for their interaction with rifampicin and isoniazid as well as their potential for cytotoxicity. Finally, AB-1 was tested for in vivo efficacy in a murine model of TB. Results: Novobiocin and AB-1 have both been shown to be active against Mtb with MIC values of 4 and 1 mg/L, respectively. Only AB-1 exhibited time-dependent bactericidal activity against drug-susceptible and drug-resistant mycobacteria, including a fluoroquinolone-resistant strain. AB-1 had potent activity in the low oxygen recovery assay model for non-replicating persistent Mtb. Additionally, AB-1 has no interaction with isoniazid and rifampicin, and has no cross-resistance with fluoroquinolones. In a murine model of TB, AB-1 significantly reduced lung cfu counts in a dose-dependent manner. Conclusions: Aminobenzimidazole inhibitors of GyrB exhibit many of the characteristics required for their consideration as a potential front-line antimycobacterial therapeutic. © The Author 2011. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source

Maiga M.,Johns Hopkins University | Agarwal N.,Johns Hopkins University | Agarwal N.,Translational Health Science and Technology Institute | Ammerman N.C.,Johns Hopkins University | And 7 more authors.

Global control of tuberculosis (TB), an infectious disease that claims nearly 2 million lives annually, is hindered by the long duration of chemotherapy required for curative treatment. Lack of adherence to this intense treatment regimen leads to poor patient outcomes, development of new or additional drug resistance, and continued spread of M.tb. within communities. Hence, shortening the duration of TB therapy could increase drug adherence and cure in TB patients. Here, we report that addition of the United Stated Food and Drug Administration-approved phosphodiesterase inhibitors (PDE-Is) cilostazol and sildenafil to the standard TB treatment regimen reduces tissue pathology, leads to faster bacterial clearance and shortens the time to lung sterilization by one month, compared to standard treatment alone, in a murine model of TB. Our data suggest that these PDE-Is could be repurposed for use as adjunctive drugs to shorten TB treatment in humans. © 2012 Maiga et al. Source

Hennig S.,University of Queensland | Naiker S.,TB Research Unit | Reddy T.,Biostatistics Unit | Egan D.,University of Liverpool | And 6 more authors.
Antimicrobial Agents and Chemotherapy

Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.) Copyright © 2015, American Society for Microbiology. All Rights Reserved. Source

Costiniuk C.T.,KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH | Costiniuk C.T.,University of Ottawa | Jenabian M.-A.,Montreal Chest Institute | Jenabian M.-A.,McGill University
Reviews in Medical Virology

SUMMARY: Failure of antiretroviral therapy to eradicate HIV, even in individuals who suppress the virus to undetectable levels, is a consequence of persistent infection in latently infected cells and within anatomical reservoirs. Support for the notion that the lungs are distinct anatomical reservoirs of HIV comes from a spectrum of studies that have documented different levels of HIV within the lungs compared with the peripheral blood. Different HIV variants have also been found within these two compartments, including variants with distinct antiretroviral resistance mutations. Given that macrophages are long-lived cellular reservoirs of HIV because of their resistance to apoptosis, HIV can persist for prolonged periods within alveolar macrophages that are abundant within the lungs. Furthermore, the large number of cells in close proximity within the lungs provides fertile grounds for cell-to-cell spread of HIV. Distinct immunological pressures in the lungs compared with the peripheral blood likely account for differences in HIV levels within these two compartments in addition to the finding of different variants within these regions. Furthermore, coinfections and tobacco may serve as local stimuli to induce further HIV replication within the lungs. Herein, we review the evidence supporting the notion that lungs are important reservoirs of HIV infection, and we discuss various factors influencing HIV burden within these reservoirs. © 2013 John Wiley & Sons, Ltd. Source

Chawla M.,Immunology Group | Parikh P.,Immunology Group | Saxena A.,Immunology Group | Munshi M.,Immunology Group | And 10 more authors.
Molecular Microbiology

Host-generated oxidative stress is considered one of the main mechanisms constraining Mycobacterium tuberculosis (Mtb) growth. The redox-sensing mechanisms in Mtb are not completely understood. Here we show that WhiB4 responds to oxygen (O2) and nitric oxide (NO) via its 4Fe-4S cluster and controls the oxidative stress response in Mtb. The WhiB4 mutant (MtbΔwhiB4) displayed an altered redox balance and a reduced membrane potential. Microarray analysis demonstrated that MtbΔwhiB4 overexpresses the antioxidant systems including alkyl hydroperoxidase (ahpC-ahpD) and rubredoxins (rubA-rubB). DNA binding assays showed that WhiB4 [4Fe-4S] cluster is dispensable for DNA binding. However, oxidation of the apo-WhiB4 Cys thiols induced disulphide-linked oligomerization, DNA binding and transcriptional repression, whereas reduction reversed the effect. Furthermore, WhiB4 binds DNA with a preference for GC-rich sequences. Expression analysis showed that oxidative stress repressed whiB4 and induced antioxidants in Mtb, while their hyper-induction was observed in MtbΔwhiB4. MtbΔwhiB4 showed increased resistance to oxidative stress in vitro and enhanced survival inside the macrophages. Lastly, MtbΔwhiB4 displayed hypervirulence in the lungs of guinea pigs, but showed a defect in dissemination to their spleen. These findings suggest that WhiB4 systematically calibrates the activation of oxidative stress response in Mtb to maintain redox balance, and to modulate virulence. © 2012 Blackwell Publishing Ltd. Source

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