Publications (163) View all
-
Article: Reply: bacille calmette-guérin vaccine: innate immunity and nonspecific effects.
American Journal of Respiratory and Critical Care Medicine 04/2013; 187(7):779-80. · 11.08 Impact Factor -
Article: Microparticles from Mycobacteria-Infected Macrophages Promote Inflammation and Cellular Migration.
[show abstract] [hide abstract]
ABSTRACT: Mycobacterium tuberculosis infection is characterized by a strong inflammatory response whereby a few infected macrophages within the granuloma induce sustained cellular accumulation. The mechanisms coordinating this response are poorly characterized. We hypothesized that microparticles (MPs), which are submicron, plasma membrane-derived vesicles released by cells under both physiological and pathological conditions, are involved in this process. Aerosol infection of mice with M. tuberculosis increased CD45(+) MPs in the blood after 4 wk of infection, and in vitro infection of human and murine macrophages with mycobacteria enhanced MP release. MPs derived from mycobacteria-infected macrophages were proinflammatory, and when injected into uninfected mice they induced significant neutrophil, macrophage, and dendritic cell recruitment to the injection site. When incubated with naive macrophages, these MPs enhanced proinflammatory cytokine and chemokine release, and they aided in the disruption of the integrity of a respiratory epithelial cell monolayer, providing a mechanism for the egress of cells to the site of M. tuberculosis infection in the lung. In addition, MPs colocalized with the endocytic recycling marker Rab11a within macrophages, and this association increased when the MPs were isolated from mycobacteria-infected cells. M. tuberculosis-derived MPs also carried mycobacterial Ag and were able to activate M. tuberculosis-specific CD4(+) T cells in vivo and in vitro in a dendritic cell-dependent manner. Collectively, these data identify an unrecognized role for MPs in host response against M. tuberculosis by promoting inflammation, intercellular communication, and cell migration.The Journal of Immunology 12/2012; · 5.79 Impact Factor -
Article: Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.
[show abstract] [hide abstract]
ABSTRACT: Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro.Organic & Biomolecular Chemistry 10/2012; · 3.70 Impact Factor -
Article: Contact investigation for tuberculosis: a systematic review and meta-analysis.
[show abstract] [hide abstract]
ABSTRACT: Investigation of contacts for patients with tuberculosis is a priority for tuberculosis control in high-income countries, and is increasingly being considered in resource-limited settings. This review was commissioned for a World Health Organization Expert Panel to develop global contact investigation guidelines.We performed a systematic review and meta-analysis of all studies reporting the prevalence of tuberculosis and latent tuberculosis infection, and the annual incidence of tuberculosis among contacts of patients with tuberculosis.After screening 9555 titles, we included 203 published studies. In 95 studies from low and middle-income settings, the prevalence of active tuberculosis in all contacts was 3.1% (95% CI 2.2%-4.4%, I(2)=99.4%), microbiologically proven tuberculosis 1.2% (95% CI 0.9-1.8%, I(2)=95.9%), and latent tuberculosis infection 51.5% (95% CI 47.1-55.8%, I(2)=98.9%). The prevalence of tuberculosis among household contacts was 3.1% (95% CI 2.1-4.5%, I(2)=98.8%) and among contacts of patients with multi-drug resistant or extensively drug resistant tuberculosis was 3.4% (95% CI 0.8-12.6%, I(2)=95.7%). Incidence was greatest in the first year after exposure. In 108 studies from high-income settings, the prevalence of TB among contacts was 1.4% (95% CI 1.1-1.8%, I(2)=98.7%), and the prevalence of latent infection was 28.1% (95% CI 24.2-32.4%, I(2)=99.5%). There was substantial heterogeneity among published studies.Contacts of tuberculosis patients are a high-risk group for developing tuberculosis, particularly within the first year. Children under 5 years and people living with HIV are particularly at risk. Policy recommendations must consider evidence of the cost-effectiveness of various contact tracing strategies, and also incorporate complementary strategies to enhance case finding.European Respiratory Journal 08/2012; · 5.89 Impact Factor -
Article: Elucidation of Mycobacterium tuberculosis type II dehydroquinase inhibitors using a fragment elaboration strategy.
[show abstract] [hide abstract]
ABSTRACT: A library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragments were initially assessed in silico which led to the selection of two small aromatic fragments for further investigation. Synthetic elaboration of the fragments provided a library of 34 inhibitors that exhibited low-micromolar inhibition of type II DHQase. A number of these inhibitors also showed antibacterial activity in the low-micromolar range in screens against M. tuberculosis in vitro; these now serve as lead compounds for further development of therapeutics for the treatment of tuberculosis.ChemMedChem 03/2012; 7(6):1031-43. · 3.15 Impact Factor
