The project is conducted as a collaboration among the Tuberculosis Research Section of LCID/NIAID, the Korean Ministry of Health, Welfare and Families Center for Disease Control, National Masan Tuberculosis Hospital (NMTH), and Yonsei University College of Medicine in the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities including a fully functional Biosafety Level 3 laboratory facility. In addition, studies are also being conducted in collaboration with Asan Medical Center, Samsung Medical Center and the National Medical Center in Seoul. Specific protocol-driven investigations underway include: (1) NIAID 05-I-N069: A Natural History Study of Multidrug-Resistant TB Stains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR tuberculosis isolates and their contribution to human disease and has over 730 subjects enrolled. A substudy of this protocol is investigating biomarkers of disease response in collaboration with University of Stellenbosch and University of Medicine and Dentistry of New Jersey. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Antituberculous Chemotherapy vs. Antituberculous Chemotherapy with Placebo in Subjects with Multi-drug Resistant Pulmonary Tuberculosis. The importance of anaerobic activity in candidate TB drugs is under investigation in this study. In 2009, the trial closed to enrollment after 33 patients enrolled because of concerns about side-effects, but follow up of these subjects and analysis of the data collected continues. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Antituberculous Therapy in Subjects with Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). For the moment LZD is infrequently used in TB patients because of its prohibitive cost and adverse effects but the emergence of XDR TB is spurring doctors into off-label, uncontrolled use in salvage therapy for the few patients that can afford it. This trial opened to enrollment in December 2008 and has enrolled 39 evaluable patients with XDR TB and closed to enrollment in July 2010. The interim analysis of the difference in time to sputum culture conversion to tuberculosis negative between the two arms of the study indicates LZD is potentially active, but the final analysis is pending until the last few subjects have reached their primary endpoint. An unexpected toxicity has been observed in this population and has been both reported to the FDA, the IRB and the sponsor and a manuscript describing the observed rabdomyolysis has been submitted. (4) NIAID 09-I-N061;Pharmacokinetics of Standard First and Second Line anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of tuberculosis chemotherapeutics into pulmonary tubercular lesions opened to enrollment in 2010;4 subjects have been enrolled by Asan Medical Center in Seoul. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients and follow up the work we have conducted on lesion penetration in rabbits. The Natural History study of MDR and XDR TB has allowed a number of basic biology questions about the differences in highly drug resistant and drug sensitive tuberculosis to be addressed by whole genome sequencing and this analysis is ongoing. We are also studying the mechanism of action of various TB drugs and how mutations in the Mtb genome confer resistance to these drugs. The mechanism of pyrazinoic acid (POA), the active form the pro-drug Pyrazinamide (PZA), was found to bind to the ribosomal protein RpsA and that the site at which it binds corresponds to the binding site of tmRNA. This RNA species is required for rescuing stalled ribosomes by trans-translation. These results not only demonstrate the novel target of this drug which has to date remained elusive, but also points to the unexpected critical role of ribosomal homeostasis in stressed cells in human pathogenesis by MTb indicating that PZA may act to poison cells by accumulation of toxic peptides released from stalled ribosomes in addition to a bottleneck in the amount of available free ribosomes in cells under in vivo stress. Further support for these studies was established by the finding that some clinical strains of MTb with PZA resistance have RpsA mutations at the POA binding site. In 2010, we reported a number of mutations in the gibB gene that encodes a putative 16S rRNA methyltransferase. Recently, by evaluating an isogenic gidB mutant strain constructed from strain H37Rv, we demonstrated the causal role of gidB in conferring a low-level SM-resistant phenotype in M. tuberculosis with a 16-fold increase in the MIC over the parent strain. Among clinical isolates, the modest increase in SM resistance conferred by a gidB mutation leads to an MIC distribution of gidB mutation-containing strains that spans the recommended SM breakpoint concentration currently used in drug susceptibility testing protocols. As such, some gidB mutation-containing isolates are found to be SM sensitive, while others are SM resistant. On the basis of a pharmacodynamic analysis and Monte Carlo simulation, those isolates that were found to be SM sensitive should still respond favorably to SM treatment, while nearly half of those found to be SM resistant would likely respond poorly. This investigation provided the first microbiological evidence for the contribution of gidB in streptomycin and demonstrates its clinical importance. Several collaborations involving new diagnostic tools are also underway including work on the next generation GenXpert test for RIF that will cover more mutations using a unique sloppy beacon approach and a XDR test for detection of fluoroquinolone resistance and Kanamycin resistance in Mtb with Dr David Alland. We are also collaborating on work on biomarkers of treatment success and to assess the presence of fragments of Mtb in easily accessible human samples, such as urine and exhaled breath condensate, for development of point of care tests. These initial studies been productive enough for us to add a substudy to the Natural History protocol and enter into a formal discovery effort.

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