Public Health Research Institute Center and
at the International Center for Public Health
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103, USA

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



Research Summary

Véronique Dartois is a new member of PHRI, with an academic appointment in the Department of Medicine at UMDNJ. 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.

Future research activities in the Dartois lab will 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 will 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 will 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 methodology soon to become available in the lab is Imaging Mass Spectrometry (IMS), an emerging label-free technology for the visualization of drugs and metabolites in biological tissues (www.maldi-msi.org). 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 lab will combine 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.




Selected Publications


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

Chen YL, Yin Z, Lakshminarayana SB, Qing M, Schul W, Duraiswamy J, Kondreddi RR, Goh A, Xu HY, Yip A, Liu B, Weaver M, Dartois V, Keller TH, Shi PY (2011) Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrob Agents Chemother 54: 3255-3261. PMI: 20516277

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

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

Dartois V, Barry CE (2010) Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Curr Clin Pharmacol 5: 96-114. PMI: 20156156

Dartois V, Leong FJ, Dick T (2008) In Seltzer P (ed.), Drug Discovery in Infectious Diseases. Wiley-VCH, Weinheim, pp. 415-440.

Dartois V, Sanchez-Quesada J, Cabezas E, Chi E, Dubbelde C, Dunn C, Granja J, Gritzen C, Weinberger D, Ghadiri MR, Parr TR, Jr. (2005) Systemic antibacterial activity of novel synthetic cyclic peptides. Antimicrob Agents Chemother 49: 3302-3310. PMI: 16048940

Dick T, Dartois V, Keller T, Matter A (2007) In S.H.E. K and P vH (eds.), Handbook of Tuberculosis; Clinics, Diagnostics, Therapy and Epidemiology. Wiley-VCH, Weinheim, pp. 139-159.

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

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

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

Kurabachew M, Lu SH, Krastel P, Schmitt EK, Suresh BL, Goh A, Knox JE, Ma NL, Jiricek J, Beer D, Cynamon M, Petersen F, Dartois V, Keller T, Dick T, Sambandamurthy VK (2008) Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis. J Antimicrob Chemother 62: 713-719. PMI: 18587134

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

Manier ML, Reyzer ML, Goh A, Dartois V, Via LE, Barry CE, 3rd, Caprioli RM (2011) Reagent precoated targets for rapid in-tissue derivatization of the anti-tuberculosis drug isoniazid followed by MALDI imaging mass spectrometry. J Am Soc Mass Spectrom 22: 1409-1419. PMI: 21953196

Nzila A, Rottmann M, Chitnumsub P, Kiara SM, Kamchonwongpaisan S, Maneeruttanarungroj C, Taweechai S, Yeung BK, Goh A, Lakshminarayana SB, Zou B, Wong J, Ma NL, Weaver M, Keller TH, Dartois V, Wittlin S, Brun R, Yuthavong Y, Diagana TT (2011) Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate. Antimicrob Agents Chemother 54: 2603-2610. PMI: 20350951

Pethe K, Sequeira PC, Agarwalla S, Rhee K, Kuhen K, Phong WY, Patel V, Beer D, Walker JR, Duraiswamy J, Jiricek J, Keller TH, Chatterjee A, Tan MP, Ujjini M, Rao SP, Camacho L, Bifani P, Mak PA, Ma I, Barnes SW, Chen Z, Plouffe D, Thayalan P, Ng SH, Au M, Lee BH, Tan BH, Ravindran S, Nanjundappa M, Lin X, Goh A, Lakshminarayana SB, Shoen C, Cynamon M, Kreiswirth B, Dartois V, Peters EC, Glynne R, Brenner S, Dick T (2010) A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat Commun 1: 57. PMI: 20975714

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

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

Shui G, Bendt AK, Jappar IA, Lim HM, Laneelle M, Herve M, Via LE, Chua GH, Bratschi MW, Rahim SZ, Michelle AL, Hwang SH, Lee JS, Eum SY, Kwak HK, Daffe M, Dartois V, Michel G, Barry CE, 3rd, Wenk MR (2012) Mycolic acids as diagnostic markers for tuberculosis case detection in humans and drug efficacy in mice. EMBO Mol Med 4: 27-37. PMI: 22147526

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

Singhal A, Mathys V, Kiass M, Creusy C, Delaire B, Aliouat el M, Dartois V, Kaplan G, Bifani P (2012) BCG induces protection against Mycobacterium tuberculosis infection in the Wistar rat model. PLoS One 6: e28082. PMI: 22162757

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

Wu T, Nagle A, Kuhen K, Gagaring K, Borboa R, Francek C, Chen Z, Plouffe D, Goh A, Lakshminarayana SB, Wu J, Ang HQ, Zeng P, Kang ML, Tan W, Tan M, Ye N, Lin X, Caldwell C, Ek J, Skolnik S, Liu F, Wang J, Chang J, Li C, Hollenbeck T, Tuntland T, Isbell J, Fischli C, Brun R, Rottmann M, Dartois V, Keller T, Diagana T, Winzeler E, Glynne R, Tully DC, Chatterjee AK (2011) Imidazolopiperazines: hit to lead optimization of new antimalarial agents. J Med Chem 54: 5116-5130. PMI: 21644570

Yeung BK, Zou B, Rottmann M, Lakshminarayana SB, Ang SH, Leong SY, Tan J, Wong J, Keller-Maerki S, Fischli C, Goh A, Schmitt EK, Krastel P, Francotte E, Kuhen K, Plouffe D, Henson K, Wagner T, Winzeler EA, Petersen F, Brun R, Dartois V, Diagana TT, Keller TH (2010) Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 53: 5155-5164. PMI: 20568778