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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


Sarathy JP, Via LE, Weiner D, Blanc L, Boshoff H, Eugenin EA, Barry CE, 3rd, Dartois VA (2018) Extreme Drug Tolerance of Mycobacterium tuberculosis in Caseum. Antimicrob Agents Chemother 62. PMI: 29203492

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

Mishra BB, Lovewell RR, Olive AJ, Zhang G, Wang W, Eugenin E, Smith CM, Phuah JY, Long JE, Dubuke ML, Palace SG, Goguen JD, Baker RE, Nambi S, Mishra R, Booty MG, Baer CE, Shaffer SA, Dartois V, McCormick BA, Chen X, Sassetti CM (2017) Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol 2: 17072. PMI: 28504669

Gopal P, Tasneen R, Yee M, Lanoix JP, Sarathy J, Rasic G, Li L, Dartois V, Nuermberger E, Dick T (2017) In Vivo-Selected Pyrazinoic Acid-Resistant Mycobacterium tuberculosis Strains Harbor Missense Mutations in the Aspartate Decarboxylase PanD and the Unfoldase ClpC1. ACS Infect Dis 3: 492-501. PMI: 28271875

Sarathy JP, Zuccotto F, Hsinpin H, Sandberg L, Via LE, Marriner GA, Masquelin T, Wyatt P, Ray P, Dartois V (2016) Prediction of Drug Penetration in Tuberculosis Lesions. ACS Infect Dis 2: 552-563. PMI: 27626295

Marakalala MJ, Raju RM, Sharma K, Zhang YJ, Eugenin EA, Prideaux B, Daudelin IB, Chen PY, Booty MG, Kim JH, Eum SY, Via LE, Behar SM, Barry CE, 3rd, Mann M, Dartois V, Rubin EJ (2016) Inflammatory signaling in human tuberculosis granulomas is spatially organized. Nat Med 22: 531-538. PMI: 27043495

Liu Y, Tan S, Huang L, Abramovitch RB, Rohde KH, Zimmerman MD, Chen C, Dartois V, VanderVen BC, Russell DG (2016) Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J Exp Med 213: 809-825. PMI: 27114608

Lanoix JP, Tasneen R, O'Brien P, Sarathy J, Safi H, Pinn M, Alland D, Dartois V, Nuermberger E (2016) High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis. Antimicrob Agents Chemother 60: 4197-4205. PMI: 27139472

Irwin SM, Prideaux B, Lyon ER, Zimmerman MD, Brooks EJ, Schrupp CA, Chen C, Reichlen MJ, Asay BC, Voskuil MI, Nuermberger EL, Andries K, Lyons MA, Dartois V, Lenaerts AJ (2016) Bedaquiline and Pyrazinamide Treatment Responses Are Affected by Pulmonary Lesion Heterogeneity in Mycobacterium tuberculosis Infected C3HeB/FeJ Mice. ACS Infect Dis 2: 251-267. PMI: 27227164

Gopal P, Yee M, Sarathy J, Low JL, Sarathy JP, Kaya F, Dartois V, Gengenbacher M, Dick T (2016) Pyrazinamide Resistance Is Caused by Two Distinct Mechanisms: Prevention of Coenzyme A Depletion and Loss of Virulence Factor Synthesis. ACS Infect Dis 2: 616-626. PMI: 27759369

Dutta NK, Bruiners N, Pinn ML, Zimmerman MD, Prideaux B, Dartois V, Gennaro ML, Karakousis PC (2016) Statin adjunctive therapy shortens the duration of TB treatment in mice. J Antimicrob Chemother 71: 1570-1577. PMI: 26903278

Dartois V, Saito K, Warrier T, Nathan C (2016) New Evidence for the Complexity of the Population Structure of Mycobacterium tuberculosis Increases the Diagnostic and Biologic Challenges. Am J Respir Crit Care Med 194: 1448-1451. PMI: 27976945

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

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

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

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

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

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

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

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



 
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