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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.
PLoS ONE | Year: 2012

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.


Loveday M.,Health Systems Research Unit | Loveday M.,University of KwaZulu - Natal | Wallengren K.,KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH | Voce A.,University of KwaZulu - Natal | And 5 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2012

SETTING: In KwaZulu-Natal, South Africa, a setting endemic for tuberculosis (TB) and the human immunodeficiency virus (HIV), prolonged hospitalisation for the treatment of the growing number of multidrug-resistant TB (MDR-TB) patients is neither possible nor effective. OBJECTIVE: To compare early treatment outcomes in patients with MDR-TB with and without HIV coi nfection at four decentralised rural sites with a central urban referral hospital. DESIGN: This is an operational, prospective cohort study of patients between 1 July 2008 and 30 November 2009, where culture conversion, time to culture conversion, survival and predictors of these outcomes were analysed. RESULTS: Of 860 patients with MDR-TB, 419 were at the decentralised sites and 441 at the central hospital. Overall, 71% were HIV co-infected. In the 17-month study period, there was a higher proportion of culture conversion at the decentralised sites compared with the centralised hospital (54% vs. 24%, P < 0.001, OR 3.76, 95%CI 2.81-5.03). The median time to treatment initiation was significantly shorter at the decentralised sites compared with the centralised hospital (72 vs. 93 days, P < 0.001). There was no significant difference in survival following treatment initiation. CONCLUSION: In this study, early treatment outcomes suggest that decentralised care for MDR-TB patients is superior to that in a centralised setting. © 2012 The Union.


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 | Year: 2014

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.


PubMed | Centers for Disease Control and Prevention, University of KwaZulu - Natal, Clinical and Biomedical Tuberculosis Research Unit, Edendale Hospital and 2 more.
Type: | Journal: Scientific reports | Year: 2016

Many hospital inpatients in South Africa have undiagnosed active and drug-resistant tuberculosis (TB). Early detection of TB is essential to inform immediate infection control actions to minimize transmission risk. We assessed the utility of Xpert() MTB/RIF (GeneXpert) as a screening tool for medical admissions at a large public hospital in South Africa. Consecutive adult patients admitted to medical wards between March-June 2013 were enrolled; sputum specimens were collected and tested by GeneXpert, smear microscopy, and culture. Chest X-rays (CXRs) were conducted as standard care for all patients admitted. We evaluated the proportion of patients identified with TB disease through each diagnostic method. Among enrolled patients whose medical charts were available for review post-discharge, 61 (27%) were diagnosed with TB; 34 (56% of diagnosed TB cases) were GeneXpert positive. When patients in whom TB was identified by other means were excluded, GeneXpert yielded only four additional TB cases. However, GeneXpert identified rifampicin-resistant TB in one patient, who was initially diagnosed based on CXR. The utility of GeneXpert for TB screening was limited in an institution where CXR is conducted routinely and which serves a population in which TB and TB/HIV co-infection are highly prevalent, but it allowed for rapid detection of rifampicin resistance.


Chawla M.,Immunology Group | Parikh P.,Immunology Group | Saxena A.,Immunology Group | Munshi M.,Immunology Group | And 10 more authors.
Molecular Microbiology | Year: 2012

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.


Grosset J.H.,Johns Hopkins University | Grosset J.H.,KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH | Ammerman N.C.,Johns Hopkins University | Ammerman N.C.,KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH
Expert Review of Anti-Infective Therapy | Year: 2013

Evaluation of: Diacon AH, Dawson R, Von Groote-Bidlingmaier F et al. Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis. Antimicrob. Agents Chemother. 57(5), 2199-2203 (2013). During the past decade considerable efforts have been made to develop and register new anti-TB drugs, making them available for patients in need. Bedaquiline (BDQ), approved by the US FDA in December 2012, is the first new anti-TB drug available for treatment of this disease since rifampicin became available in 1967. BDQ has the peculiarity of being a drug with a very long half-life and potent antimicrobial activity that becomes noticeable only after the first 4 days of treatment. Consequently, Diacon et al. have conducted a 14-day dose-ranging study aimed at assessing the early bactericidal activity of BDQ in TB patients who received loading doses of the drug during the first 2 days of treatment. The loading doses partially overcame the delayed antimicrobial activity only in patients treated daily with as much as 400 mg. © 2013 Informa UK Ltd.


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 | Year: 2012

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.


PubMed | KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH, IBM, Harvard University and Center for Tuberculosis Research
Type: | Journal: EBioMedicine | Year: 2016

Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to -lactam antibiotics. However, there is evidence that susceptibility to -lactam antibiotics in combination with -lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to -lactam/-lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two -lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a -lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, paradoxical hypersusceptibility to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for -lactam/-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis.


Kasprowicz V.O.,Harvard University | Kasprowicz V.O.,Kwazulu Natal Research Institute for Tuberculosis and HIV K RITH | Kasprowicz V.O.,Doris Duke Medical Research Institute | Halliday J.S.,University of Oxford | And 3 more authors.
Biomarkers in Medicine | Year: 2012

IFN-γ release by antigen-specific T cells can be used to track immune responses to infections and vaccines. In recent years, there have been substantial advances in the techniques available to measure IFN-γ release and a generation of such assays are now available for clinical use, as well as in a research setting. Interferon release leads to subsequent release of interferon-responsive chemokines such as MIG and IP-10, thus amplifying the original signal. A number of investigators have assessed whether measurement of these chemokines might provide a sensitive platform for detection of infection and antigen-specific T-cell responses. In this article, we assess the potential of these new approaches. We have termed the new antigen-specific T-cell assays monokine-amplified IFN-γ release assays (MIGRAs). Overall, it seems likely that improvements in the detection threshold could be made by analysis of antigen-triggered chemokines and potentially of other molecules in the future, although whether MIGRAs will provide additional clinical utility still remains to be determined. © 2012 Future Medicine Ltd.


PubMed | KwaZulu Natal Research Institute for Tuberculosis and HIV K RITH and U.S. National Institutes of Health
Type: | Journal: Nature communications | Year: 2016

The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtbs respiration using extracellular flux technology. We find that Mtbs ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimines production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb.

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