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Scientific Overview Research Interest Summary Principal Investigators    Yuri Bushkin, Ph.D.
   Theresa Chang, Ph.D.
   Neeraj Chauhan, Ph.D.
   Véronique Dartois, Ph.D.
   Thomas Dick, Ph.D.
   Karl Drlica, Ph.D.
   David Dubnau, Ph.D.
   Eliseo A. Eugenin, Ph.D.
   Marila Gennaro, M.D.
   Fred Kramer, Ph.D.
   Barry Kreiswirth, Ph.D.
   Min Lu, Ph.D.
   Leonard Mindich, Ph.D.
   Arkady Mustaev, Ph.D.
   Jyothi Nagajyothi, Ph.D.
   David Perlin, Ph.D.
   Abraham Pinter, Ph.D.
   Marcela Rodriguez, Ph.D.
   Lanbo Shi, Ph.D.
   Selvakumar Subbian, Ph.D.
   Sanjay Tyagi, Ph.D.
   Christopher Vinnard, M.D.
   Chaoyang Xue, Ph.D.
   Xilin Zhao, Ph.D.

   Research Faculty
   Liang Chen, Ph.D.
   Eugenie Dubnau, Ph.D.
   Jeanette Hahn, Ph.D.
   Salvatore Marras, Ph.D.
   Yanan Zhao, Ph.D.

Emeritus Faculty Recent Publications
Véronique Dartois, Ph.D.

Research Summary  |  Selected Publications

Public Health Research Institute Center
at the International Center for Public Health
New Jersey Medical School - Rutgers, The State University of New Jersey
225 Warren Street
Newark, New Jersey 07103, USA

Phone: (973) 854-3160
Fax: (973) 854-3201
e-mail: dartoiva@njms.rutgers.edu

Research Summary

Véronique Dartois joined PHRI in April 2012, with an academic appointment in the Department of Medicine at Rutgers, the State University of New Jersey. Initially trained as a molecular biologist, Dr Dartois comes with 7 years of experience in the pharmaceutical industry, acquired through her previous position as Pharmacology Unit Head at the Novartis Institute of Tropical Diseases in Singapore. Her current research interests include the pharmacokinetics and imaging of anti-tuberculosis drugs in pulmonary lesions, the molecular mechanisms driving intracellular accumulation of TB drugs in Mycobacterium and in macrophages, and the optimization of predictive animal models and in vitro assays to study these questions.

With funding from the Gates Foundation and the NIH, research activities in the Dartois lab focus on the pharmacokinetics and pharmacodynamics of anti-tuberculosis agents in pulmonary TB lesions, in the rabbit model and through clinical research studies. Specifically, lesion-specific analysis of drug exposure and bacterial killing help identify and characterize lung granuloma compartments in which organisms are not eliminated. In the context of failing TB control programs and global emergence of drug resistance, this information can guide a more rational approach to designing treatment regimens that ensure optimal drug exposure at the site of infection. Recent reports suggesting that many of the 1st line drugs may be sub-optimally dosed highlight the importance of these studies.

A state-of-the-art Imaging Mass Spectrometry (IMS) platform is now available in the Dartois Lab, for the visualization of drugs and metabolites in biological tissues. IMS preserves spatial profile and tissue architecture, enabling the relative quantification and 2D distribution of the drugs and their metabolites within healthy and diseased tissues. The group combines the accuracy of conventional mass spectrometry with the spatial resolution of IMS to measure the levels of anti-tuberculous agents in various lesion types versus uninvolved lung tissue and plasma, and visualize relative drug distribution and concentration gradients across the different layers of individual granulomas and cavities. This technology can be expanded to a large variety of drug molecules active against an array of diseases, and holds great promise for the molecular imaging of the biochemical and pathological changes caused to the host by any disease of interest.

Below we describe a rapid equilibrium dialysis (RED) method to measure drug binding to caseum from pulmonary tuberculosis lesions and cavities. The protocol is also used with a foamy macrophage-derived matrix that is an effective surrogate to caseum. This video was published at JoVE.

An In Vitro Caseum Binding Assay that Predicts Drug Penetration in Tuberculosis Lesions

Selected Publications

Zimmerman M, Lestner J, Prideaux B, O'Brien P, Freedman I, Chen C, Dietzold J, Daudelin I, Kaya F, Blanc L, Chen PY, Park S, Salgame P, Sarathy J, Dartois V (2017) Ethambutol partitioning in tuberculous pulmonary lesions explains its clinical efficacy. Antimicrob Agents Chemother. PMI: 28696241

Via LE, Savic R, Weiner DM, Zimmerman MD, Prideaux B, Irwin SM, Lyon E, O'Brien P, Gopal P, Eum S, Lee M, Lanoix JP, Dutta NK, Shim T, Cho JS, Kim W, Karakousis PC, Lenaerts A, Nuermberger E, Barry CE, 3rd, Dartois V (2015) Host-Mediated Bioactivation of Pyrazinamide: Implications for Efficacy, Resistance, and Therapeutic Alternatives. ACS Infect Dis 1: 203-214. PMI: 26086040

Via LE, England K, Weiner DM, Schimel D, Zimmerman MD, Dayao E, Chen RY, Dodd LE, Richardson M, Robbins KK, Cai Y, Hammoud D, Herscovitch P, Dartois V, Flynn JL, Barry CE, 3rd (2015) A sterilizing tuberculosis treatment regimen is associated with faster clearance of bacteria in cavitary lesions in marmosets. Antimicrob Agents Chemother 59: 4181-4189. PMI: 25941223

Prideaux B, Via LE, Zimmerman MD, Eum S, Sarathy J, O'Brien P, Chen C, Kaya F, Weiner DM, Chen PY, Song T, Lee M, Shim TS, Cho JS, Kim W, Cho SN, Olivier KN, Barry CE, 3rd, Dartois V (2015) The association between sterilizing activity and drug distribution into tuberculosis lesions. Nat Med. PMI: 26343800

Prideaux B, ElNaggar MS, Zimmerman M, Wiseman JM, Li X, Dartois V (2015) Mass spectrometry imaging of levofloxacin distribution in TB-infected pulmonary lesions by MALDI-MSI and continuous liquid microjunction surface sampling. Int J Mass Spectrom 377: 699-708. PMI: 26185484

Lenaerts A, Barry CE, 3rd, Dartois V (2015) Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev 264: 288-307. PMI: 25703567

Lakshminarayana SB, Huat TB, Ho PC, Manjunatha UH, Dartois V, Dick T, Rao SP (2015) Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents. J Antimicrob Chemother 70: 857-867. PMI: 25587994

DeMarco VP, Ordonez AA, Klunk M, Prideaux B, Wang H, Zhuo Z, Tonge PJ, Dannals RF, Holt DP, Lee CK, Weinstein EA, Dartois V, Dooley KE, Jain SK (2015) Determination of [11C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging. Antimicrob Agents Chemother 59: 5768-5774. PMI: 26169396

Dartois V (2014) The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nat Rev Microbiol 12: 159-167. PMI: 24487820

Coleman MT, Chen RY, Lee M, Lin PL, Dodd LE, Maiello P, Via LE, Kim Y, Marriner G, Dartois V, Scanga C, Janssen C, Wang J, Klein E, Cho SN, Barry CE, 3rd, Flynn JL (2014) PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Sci Transl Med 6: 265ra167. PMI: 25473035

Zhang YJ, Reddy MC, Ioerger TR, Rothchild AC, Dartois V, Schuster BM, Trauner A, Wallis D, Galaviz S, Huttenhower C, Sacchettini JC, Behar SM, Rubin EJ (2013) Tryptophan biosynthesis protects mycobacteria from CD4 T-cell-mediated killing. Cell 155: 1296-1308. PMI: 24315099

Sarathy JP, Lee E, Dartois V (2013) Polyamines inhibit porin-mediated fluoroquinolone uptake in mycobacteria. PLoS One 8: e65806. PMI: 23755283

Sarathy J, Dartois V, Dick T, Gengenbacher M (2013) Reduced drug uptake in phenotypically resistant nutrient-starved nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 57: 1648-1653. PMI: 23335744

Lin PL, Coleman T, Carney JP, Lopresti BJ, Tomko J, Fillmore D, Dartois V, Scanga C, Frye LJ, Janssen C, Klein E, Barry CE, 3rd, Flynn JL (2013) Radiologic responses in cynomolgous macaques for assessing tuberculosis chemotherapy regimens. Antimicrob Agents Chemother. PMI: 23796926

Dartois V, Barry CE, 3rd (2013) A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis. Bioorg Med Chem Lett 23: 4741-4750. PMI: 23910985

Carroll MW, Jeon D, Mountz JM, Lee JD, Jeong YJ, Zia N, Lee M, Lee J, Via LE, Lee S, Eum SY, Lee SJ, Goldfeder LC, Cai Y, Jin B, Kim Y, Oh T, Chen RY, Dodd LE, Gu W, Dartois V, Park SK, Kim CT, Barry CE, 3rd, Cho SN (2013) Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis. Antimicrob Agents Chemother 57: 3903-3909. PMI: 23733467

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 (2012) Infection dynamics and response to chemotherapy in a rabbit model of tuberculosis using [(1)(8)F]2-fluoro-deoxy-D-glucose positron emission tomography and computed tomography. Antimicrob Agents Chemother 56: 4391-4402. PMI: 22687508

Sarathy J, Dartois V, Lee D (2012) The role of transport mechanisms in mycobacterium tuberculosis drug resistance and tolerance. Pharmaceuticals 5: 1210-1235. PMI:

Lin PL, Dartois V, Johnston PJ, Janssen C, Via L, Goodwin MB, Klein E, Barry CE, 3rd, Flynn JL (2012) Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc Natl Acad Sci U S A 109: 14188-14193. PMI: 22826237

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 (2012) Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med 367: 1508-1518. PMI: 23075177

Kjellsson MC, Via LE, Goh A, Weiner D, Low KM, Kern S, Pillai G, Barry CE, 3rd, Dartois V (2012) Pharmacokinetic evaluation of the penetration of antituberculosis agents in rabbit pulmonary lesions. Antimicrob Agents Chemother 56: 446-457. PMI: 21986820

Franzblau SG, DeGroote MA, Cho SH, Andries K, Nuermberger E, Orme IM, Mdluli K, Angulo-Barturen I, Dick T, Dartois V, Lenaerts AJ (2012) Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis. Tuberculosis (Edinb) 92: 453-488. PMI: 22940006

Subbian S, Tsenova L, O'Brien P, Yang G, Koo MS, Peixoto B, Fallows D, Dartois V, Muller G, Kaplan G (2011) Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLoS Pathog 7: e1002262. PMI: 21949656

Singhal A, Aliouat el M, Herve M, Mathys V, Kiass M, Creusy C, Delaire B, Tsenova L, Fleurisse L, Bertout J, Camacho L, Foo D, Tay HC, Siew JY, Boukhouchi W, Romano M, Mathema B, Dartois V, Kaplan G, Bifani P (2011) Experimental tuberculosis in the Wistar rat: a model for protective immunity and control of infection. PLoS One 6: e18632. PMI: 21533270

Prideaux B, Dartois V, Staab D, Weiner DM, Goh A, Via LE, Barry CE, 3rd, Stoeckli M (2011) High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. Anal Chem 83: 2112-2118. PMI: 21332183

Heng Y, Seah PG, Siew JY, Tay HC, Singhal A, Mathys V, Kiass M, Bifani P, Dartois V, Herve M (2011) Mycobacterium tuberculosis infection induces hypoxic lung lesions in the rat. Tuberculosis (Edinb) 91: 339-341. PMI: 21636324

Foo DG, Tay HC, Siew JY, Singhal A, Camacho L, Bifani P, Dartois V, Herve M (2011) T cell monitoring of chemotherapy in experimental rat tuberculosis. Antimicrob Agents Chemother 55: 3677-3683. PMI: 21628535

Dartois V (2011) Drug forgiveness and interpatient pharmacokinetic variability in tuberculosis. J Infect Dis 204: 1827-1829. PMI: 22021619

Cherian J, Choi I, Nayyar A, Manjunatha UH, Mukherjee T, Lee YS, Boshoff HI, Singh R, Ha YH, Goodwin M, Lakshminarayana SB, Niyomrattanakit P, Jiricek J, Ravindran S, Dick T, Keller TH, Dartois V, Barry CE, 3rd (2011) Structure-activity relationships of antitubercular nitroimidazoles. 3. Exploration of the linker and lipophilic tail of ((s)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybe nzyl)amine (6-amino PA-824). J Med Chem 54: 5639-5659. PMI: 21755942

Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, Gonzalez-Paez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT (2010) Spiroindolones, a potent compound class for the treatment of malaria. Science 329: 1175-1180. PMI: 20813948

Leong FJ, Dartois V, Dick T (2010) A Color Atlas of Comparative Pathology of Pulmonary Tuberculosis. CRC Press

Yin Z, Chen YL, Schul W, Wang QY, Gu F, Duraiswamy J, Kondreddi RR, Niyomrattanakit P, Lakshminarayana SB, Goh A, Xu HY, Liu W, Liu B, Lim JY, Ng CY, Qing M, Lim CC, Yip A, Wang G, Chan WL, Tan HP, Lin K, Zhang B, Zou G, Bernard KA, Garrett C, Beltz K, Dong M, Weaver M, He H, Pichota A, Dartois V, Keller TH, Shi PY (2009) An adenosine nucleoside inhibitor of dengue virus. Proc Natl Acad Sci U S A 106: 20435-20439. PMI: 19918064

Barry CE, 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7: 845-855. PMI: 19855401

Dartois V, Leong FJ, Dick T (2008) TB drug discovery: issues, gaps and the way forward. In Seltzer P (ed.), Drug Discovery in Infectious Diseases. Wiley-VCH, Weinheim, pp. 415-440.

Dick T, Dartois V, Keller T, Matter A (2007) TB drug discovery from target identification to proof of concept studies. In S.H.E. K and P vH (eds.), Handbook of Tuberculosis; Clinics, Diagnostics, Therapy and Epidemiology. Wiley-VCH, Weinheim, pp. 139-159.

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