Tuberculosis (TB) is one of the leading infectious diseases in the world, with approximately one-third of the world’s population harboring the causative agent, Mycobacterium tuberculosis (Mtb). Though previously a disease associated with aristocratic societies, TB is now predominantly a third-world disease, particularly affecting Asian communities and sub-Saharan Africa. Mtb isolates are increasingly resistant to drug therapies: multidrug-resistant TB (MDR TB) or more severely, extensively drug-resistant TB (XDR TB). As a consequence of these emerging strains, it is becoming increasingly apparent that novel drugs are necessary to combat Mtb infections.
The Tuberculosis Research Section (TBRS) is a multidisciplinary group of research scientists comprised of biologists, chemists, and clinical researchers who share a common interest in TB. TBRS projects focus on understanding the scientific issues that facilitate the development of drugs that will make a genuine difference in the outcome for TB subjects globally. TBRS scientists are highly interactive worldwide in this endeavor, and as a result of our outstanding collaborators, TBRS has the distinction of being the most highly-cited research group in the world in the field of TB over the past 10 years. They were cited in Nature Medicine’s “The top twenty research papers on tuberculosis” (13(3):276-7, 2007). Learn more about TBRS’s ranking among TB researchers worldwide.
The International Tuberculosis Research Center (ITRC) is the product of an on-going collaboration between NIAID and the South Korean Ministry of Health and Welfare. Research scientists at ITRC focus on human clinical trials of TB, particularly MDR TB and XDR TB.
ITRC is divided into three sections: Immunology and Pathology, Bacteriology, and Clinical Research. ITRC scientists are designing and evaluating rapid molecular diagnostics for determining TB drug resistance, surrogate immunologic markers for determining effective response to TB chemotherapy, and understanding the epidemiology of MDR and XDR TB in Korea.
Dr. Barry received his Ph.D. in organic and bio-organic chemistry in 1989 from Cornell University. He joined NIAID following postdoctoral research at Johns Hopkins University. In 1998, he was tenured as chief of the TBRS. Dr. Barry is a member of several editorial boards, has authored more than 120 research publications in tuberculosis, and is the most cited researcher in the field, according to ScienceWatch.com.
Steve HollandKen Olivier
AECOM: John Blanchard’s laboratory at the Albert Einstein College of MedicineCAMA: Chris Abels’ laboratory at Cambridge UniversityCAMH: Elizabeth Hall’s laboratory at Cambridge UniversityGNF: The Genomics Institute of the Novartis FoundationICY: Douglas Young’s laboratory at Imperial CollegeKRICT: Korea Institute for Chemical Technology, DaejonLANL: Basil Swanson’s laboratory at Los Alamos National LaboratoriesNCGC: NIH Chemical Genomics CenterNITD: The Novartis Institute for Tropical Diseases, SingaporeNUS: Marcus Wenk’s laboratory at the National University of SingaporeOXU: Ben Davis’ laboratory at Oxford UniversityPITT: Joanne Flynn’s laboratory at the University of PittsburghSBRI: David Sherman’s laboratory at the Seattle Biomedical Research InstituteSRI: Kim Janda’s laboratory at the Scripps Research InstituteUMDNJA: David Alland’s laboratory at the University of Medicine and Dentistry of New JerseyUMDNJK: Gilla Kaplan’s laboratory at the University of Medicine and Dentistry of New JerseyUMN: Courtney Aldrich’s laboratory at the University of MinnesotaYUS: Sang Nae Cho’s laboratory at Yonsei University, SeoulYUW: Hae Young Lee’s laboratory at Yonsei University, Wonju
Dartois V, Barry CE 3rd. A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis. Bioorg Med Chem Lett. 2013 Sep 1;23(17):4741-50.
Via LE, Weiner DM, Schimel D, Lin PL, Dayao E, Tankersley SL, Cai Y, Coleman MT, Tomko J, Paripati P, Orandle M, Kastenmayer RJ, Tartakovsky M, Rosenthal A, Portevin D, Eum SY, Lahouar S, Gagneux S, Young DB, Flynn JL, Barry CE 3rd. Differential virulence and disease progression following Mycobacterium tuberculosis complex infection of the common marmoset (Callithrix jacchus). Infect Immun. 2013 Aug;81(8):2909-19.
Lee IY, Gruber TD, Samuels A, Yun M, Nam B, Kang M, Crowley K, Winterroth B, Boshoff HI, Barry CE 3rd. Structure-activity relationships of antitubercular salicylanilides consistent with disruption of the proton gradient via proton shuttling. Bioorg Med Chem. 2013 Jan 1;21(1):114-26.
Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, Via LE, Goldfeder LC, Kang E, Jin B, Park H, Kwak H, Kim H, Jeon HS, Jeong I, Joh JS, Chen RY, Olivier KN, Shaw PA, Follmann D, Song SD, Lee JK, Lee D, Kim CT, Dartois V, Park SK, Cho SN, Barry CE 3rd. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012 Oct 18;367(16):1508-18.
Kumar P, Arora K, Lloyd JR, Lee IY, Nair V, Fischer E, Boshoff HI, Barry CE 3rd. Meropenem inhibits D,D-carboxypeptidase activity in Mycobacterium tuberculosis. Mol Microbiol. 2012 Oct;86(2):367-81.
Via LE, Schimel D, Weiner DM, Dartois V, Dayao E, Cai Y, Yoon YS, Dreher MR, Kastenmayer RJ, Laymon CM, Carny JE, Flynn JL, Herscovitch P, Barry CE 3rd. Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [18F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother. 2012 Aug;56(8):4391-402.
Visit PubMed for a complete publication listing.
TBRS works on myriad projects, ranging from drugs currently in clinical trials through cell and molecular biology and down to basic chemistry.
Linezolid is an oxazolidinone drug commonly used short-term for various bacterial infections. Despite relatively modest in vitro potency against TB, off-label use in chronic treatment failures with highly drug-resistant TB suggests the drug has a potent effect in clinical use. Our Phase II trial is designed to understand this unexpected clinical efficacy in chronic XDR TB-infected subjects and to explore alternative dosing strategies to minimize unwanted side effects of this drug. This trial aims to establish a new paradigm for trials of future chemotherapies by intensively studying the effect of a new agent in a small number of non-responsive subjects. Learn more about the linezolid clinical trial.
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Positron emission tomography (PET) scans illuminate areas of inflammation using radiolabeled tracers. Computed tomography (CT) takes high-resolution X-ray images of the body, allowing reconstruction of the 3-D structure of the scanned region. By simultaneously performing PET/CT scans, we can monitor Mtb infections in subjects over time to correlate lung structure and functional Mtb activity and measure the impact of new and existing chemotherapies.
PET/CT is an important endpoint in our on-going clinical trials, and we hope to develop this as a surrogate endpoint for trials of new drugs for TB. We have developed the ability to monitor PET/CT changes in animal models of TB and are developing Mtb-specific PET probes to improve this technology.
The accurate diagnosis of a TB infection can take weeks or even months and relies on antiquated methods. To help reduce this time, we are currently investigating new markers that potentially hasten the accurate diagnosis of Mtb and improve our ability to monitor the response of subjects to chemotherapy. Biomarker sampling is also integrated into all of our ongoing clinical trials to allow these to be tested as possible prospective markers for outcome. We are currently focusing on the following:
Hypoxic environments are reportedly experienced by Mtb during human infection and are critical in determining the length of time required for achieving a durable cure for TB. Metronidazole is an agent that only has activity against Mtb under hypoxic conditions, and this Phase II clinical trial in MDR TB subjects is designed to test the hypothesis that lesions that appear hypoxic will respond to this agent. The trial is pioneering the use of quantitative high-resolution CT (HRCT) as an endpoint in studies of the response of specific lesions to TB chemotherapy. Information from this trial will inform future targets that are selected early in the development of new anti-tuberculosis agents.
Learn more about the metronidazole clinical trial.
South Korea has experienced a nine-fold decrease in the number of new TB cases during the last four decades. The number of cases involving MDR TB or XDR TB, however, is on the rise. This prospective cohort study intends to follow subjects infected with highly drug-resistant strains and begin to understand the bacterial and host factors that contribute to the development of drug resistance. To better understand the genetic diversity of these resistant Mtb strains, we have been genotyping isolated strains from subjects and comparing these results to phenotypic tests meant to understand their pathogenicity and drug-resistance. These samples and results should allow us to test and improve the predictive ability of molecular tests for determining drug resistance.
Learn more about the MDR TB clinical trial in Korea.
One of the primary problems in new drug discovery for TB is the selection of appropriate targets that will have a therapeutic impact and kill the bacteria. This project seeks to screen for activity against whole cells of Mtb and then use these as starting points for target identification. By performing a variety of screens against Mtb under in vivo-relevant conditions (such as hypoxia, growth on lipid sources, and starvation), we have started assembling a “toolbox” of compounds that specifically inhibit growth of the pathogen under these conditions. One unique source of compounds is the “grey-layer” decomposition zone deep within sphagnum bogs (peat moss). This environment is highly acidic and microaerophilic, similar to that within human lungs where Mtb is thought to reside. Natural selection has endowed other microorganisms living in these nutrient-bare sphagnum areas with the ability to compete with endogenous slow-growing mycobacteria for these scarce nutrients by secreting secondary metabolites. Using microarray analysis and whole genome re-sequencing to identify the targets of these compounds, we can then identify potentially druggable leads.
We are also using a high throughput screening (HTS) robot to help quickly screen for potential drug targets that are revealed as necessary for Mtb survival under a range of growth conditions. These conditions, such as hypoxia, starvation, etc., mimic conditions that Mtb might encounter during the course of disease in a human host. We have adopted a quantitative HTS approach that screens all compounds as a titration series in order to get dose-response curves. The targets inhibited by these compound hits are subsequently identified by a variety of methods, including microarray analysis to compare profiles to our existing database of drug-induced transcriptional profiles, whole genome sequencing of resistant mutants, and macromolecular incorporation assays. Thus the multitude of hits that are identified by HTS will enable rapid discovery of multiple inhibitor-susceptible pathways that contain steps that are bottlenecks in the metabolism essential for survival under these conditions.
The peptidoglycan (PG) layer of mycobacteria is similar in structure to other bacteria but retains some distinction by maintaining a dynamic composition. Specifically, the number and location of cross-links within the PG layer vary with respect to the replication phase of the bacteria. This makes drugs that interfere with or inhibit the genes or metabolic pathways involved in the recycling of the PG layer an excellent target for chemotherapies. This pathway has provided effective drugs for many other bacterial pathogens, like beta-lactam antibiotics such as penicillin, and we are attempting to uncover possible candidates among the existing drugs and to develop TB-specific agents to leverage the broad experience in this compound class.
Understanding how drugs exert their antibacterial effects is an essential component of both improving those agents and monitoring resistance in subjects taking them. Ethambutol is a front-line agent that disrupts arabinogalactan synthesis in the bacterial cell wall that is widely thought to be the least potent of the four drugs in this regimen. SQ109 is a diamine analog of ethambutol with increased potency and a different mode of action that was first synthesized at TBRS in partnership with Sequella. The bicyclic nitroimidazole PA-824 is in Phase II clinical trials and induces the killing of both replicating and non-replicating Mtb. A bacterial enzyme and the co-factor F420 metabolize PA-824 and in the process liberate lethal reactive nitrogen species, including nitric oxide.
Learn more about Sequella and SQ109 development (PDF).
Read the Science article on PA-824 and the NIAID press release on it.
Check out the TB Alliance for more information.
Co-factors, or vitamins, are essential nutrients that the bacterium must either make or scavenge from an infected host to sustain an infection. We are exploring several co-factor pathways as potential points of intervention for new anti-tuberculars, since deprivation of these vitamins would have effects on every enzyme that uses them. Certain steps in the NAD biosynthetic pathway have strong potential, which are being explored using both high-throughput screening and structure-based design strategies. Likewise, biotin is an essential nutrient, and inhibition of synthesis of the biotin precursors diaminopelargonic/ketoaminopelargonic acid is also targeted for drug development. In each case, a thorough understanding of the mechanisms for biosynthesis and salvage provides essential information that allows vulnerable steps to be pinpointed.
Nitroimidazoles offer considerable promise as potential anti-tuberculars, and two are currently in clinical trials. Optimism for these drugs arises from the fact that they have activity against both aerobic and anaerobic Mtb, but these two activities are not directly related to each other. Considerable room for optimization of these compounds remains, and we expend a lot of effort attempting to understand how these molecules work and how to improve them. Using computational techniques (such as QSAR modeling) combined with synthesis of new molecules within this class, we hope to design a novel candidate molecule that ultimately becomes a widely used drug for the treatment of tuberculosis.
Last Updated August 20, 2013