Members

Weill Cornell Medicine

Nathan Lab Website

Department of Microbiology and Immunology

New York, New York USA

Amrita Singh, Kyu Rhee, Carl Nathan and Ben Gold- Photo by Kristin Burns-Huang (2022)

Member since 2012

Representative

Carl Nathan, MD Professor and Chair of the Department of Microbiology and Immunology

Associate Representatives

Kyu Rhee, MD PhD, Professor

Dirk Schnappinger, PhD,Associate Professor

Team

  • Ben Gold, Ph.D.
  • Amrita Singh, Ph.D.
  • Jun Zhang, Ph.D.
  • Julia Roberts
  • Christine Suh
  • Thulasi Warrier, Ph.D.
  • Landys Lopez-Quezada, PhD
  • Yan Ling, MS

Nathan Lab

About

The TBDA is a unique experiment in the sociological organization of biomedical cooperation (1). I’ve had the privilege of participating in the TBDA from before its beginning (2), when I helped in the design of its charter. I’ve participated since then, with and without funding from the Bill & Melinda Gates Foundation, with complementary work being supported by the NIH, including through the Tri-Institutional TB Research Unit that I led from 2014-2021.

Role & Expertise

My lab’s role grew out of our serendipitous discovery of a compound that was mycobactericidal for M. tuberculosis (Mtb) only when the bacilli were non-replicating, no matter what conditions imposed non-replication (3). This was apparently the first compound with those properties. The compound inhibits dihydrolipoamide acyltransferase, an enzyme in central carbon metabolism, both when tested against the recombinant protein and against intact Mtb, spares the homologous human enzyme, and is non-toxic to mammalian cells. However, it is not sufficiently drug-like. This finding turned on a mental light bulb: we realized that it should be possible to identify more compounds that kill non-replicating Mtb by screening compound libraries against non-replicating Mtb. To our knowledge, this had never been done, nor was it obvious how to do it.

Non-replication of bacteria is closely associated with a state of phenotypic antimicrobial resistance to most antimicrobials that are identified in the conventional manner, that is, by their action against replicating bacteria (4, 5). We reasoned that compounds that avoid this form of phenotypic resistance and kill non-replicating Mtb might help eliminate the “persisters” that are believed to contribute to the need for lengthy drug regimens to cure TB. These regimens use drugs that are chiefly active on replicating Mtb (such as isoniazid, rifampin and ethambutol) or only active against non-replicating Mtb, but under a limited set of conditions (such as pyrazinamide).

First, we had to solve the problem of how to conduct a high-throughput screen for compounds that inhibit bacterial growth under conditions that are chosen to inhibit bacterial growth without test compounds. The answer was a two-stage assay: exposure to the compounds under non-replicating conditions, followed by transfer to replicating conditions and monitoring the ability of the bacteria to resume growth. This required development of ancillary assays to distinguish when growth inhibition resulted from carry-over of compound from the first stage of the assay to the second stage (6).

We worked closely with GSK, Sanofi and Evotec. Two postdoctoral fellows, Thulasi Warrier and Landys Lopez-Quezada, undertook extended residences at GSK through the auspices of the Tres Cantos Open Lab program. Some of the findings are reported in references 7-10.

In parallel efforts supported by NIH, we found additional examples of compounds selectively bactericidal for non-replicating Mtb. These are inhibitors of the mycobacterial proteasome (10, 11) and of lipoamide dehydrogenase (12,13) (the citations are to the first and the most recent papers in each of these ongoing projects). These compounds spare the cognate host enzymes.

The challenge now is to identify an animal model of tuberculosis in which it is possible to discern the impact of compounds that kill non-replicating Mtb on a persister population whose size is unknown and that may be too small to appreciate from changes in the organ burden of CFU measured on a log10 scale. We hope mouse models of relapse may allow this (e.g., 11).

Our screening of compound libraries under non-replicating conditions chosen to model physiological influences (mild nitrosative and acid stress, hypoxia, and a fatty acid carbon source) was accompanied by assays under conventional conditions that support Mtb’s logarithmic replication. Among the hits selectively active under replicating conditions was the first drug-like, mycobactericidal inhibitor of Mtb’s phosphopanthetheine transferase (PptT) (14). Our current TBDA efforts are focused on finding improved inhibitors of PptT.

Teamwork is the essence of the TBDA. The PptT inhibitor project illustrates that. Our TBDA-member partners in this effort are Global Alliance, Evotec, GSK and Jim Sacchettini’s lab at Texas A & M. Also joining the team via NIH support is the Aubé lab at University of North Carolina.

Intersecting with that team are the other labs on the Global Health floor of the Belfer Research Building at Weill Cornell Medicine, all of whom are treasured, long-term collaborators—TBDA members Kyu Rhee and Dirk Schnappinger, Sabine Ehrt, and Dan Fitzgerald and his colleagues aat the Center for Global Health, with its research, teaching and clinical activities in Haiti, Tanzania and elsewhere.

Links

Nathan Lab

References

  1. Nathan, C. Cooperative Development of Antimicrobials: Looking Back to Look Ahead. Nature Reviews Microbiology 2015, 13 (10), 651–657. https://doi.org/10.1038/nrmicro3523.
  2. Aldridge, B. B.; Barros-Aguirre, D.; Barry, C. E.; Bates, R. H.; Berthel, S. J.; Boshoff, H. I.; Chibale, K.; Chu, X.-J.; Cooper, C. B.; Dartois, V.; Duncan, K.; Fotouhi, N.; Gusovsky, F.; Hipskind, P. A.; Kempf, D. J.; Lelièvre, J.; Lenaerts, A. J.; McNamara, C. W.; Mizrahi, V.; Nathan, C.; Olsen, D. B.; Parish, T.; Petrassi, H. M.; Pym, A.; Rhee, K. Y.; Robertson, G. T.; Rock, J. M.; Rubin, E. J.; Russell, B.; Russell, D. G.; Sacchettini, J. C.; Schnappinger, D.; Schrimpf, M.; Upton, A. M.; Warner, P.; Wyatt, P. G.; Yuan, Y. The Tuberculosis Drug Accelerator at Year 10: What Have We Learned? Nature Medicine 2021, 27 (8), 1333–1337. https://doi.org/10.1038/s41591-021-01442-2.
  3. Bryk, R.; Gold, B.; Venugopal, A.; Singh, J.; Samy, R.; Pupek, K.; Cao, H.; Popescu, C.; Gurney, M.; Hotha, S.; Cherian, J.; Rhee, K.; Ly, L.; Converse, P. J.; Ehrt, S.; Vandal, O.; Jiang, X.; Schneider, J.; Lin, G.; Nathan, C. Selective Killing of Nonreplicating Mycobacteria. Cell Host & Microbe 2008, 3 (3), 137–145. https://doi.org/10.1016/j.chom.2008.02.003.
  4. Nathan, C. Fresh Approaches to Anti-Infective Therapies. Science Translational Medicine 2012, 4 (140). https://doi.org/10.1126/scitranslmed.3003081.
  5. Schrader, S. M.; Vaubourgeix, J.; Nathan, C. Biology of Antimicrobial Resistance and Approaches to Combat It. Science Translational Medicine 2020, 12 (549). https://doi.org/10.1126/scitranslmed.aaz6992.
  6. Gold, B.; Roberts, J.; Ling, Y.; Quezada, L. L.; Glasheen, J.; Ballinger, E.; Somersan-Karakaya, S.; Warrier, T.; Warren, J. D.; Nathan, C. Rapid, Semiquantitative Assay To Discriminate among Compounds with Activity against Replicating or Nonreplicating Mycobacterium Tuberculosis. Antimicrobial Agents and Chemotherapy 2015, 59 (10), 6521–6538. https://doi.org/10.1128/AAC.00803-15.
  7. Warrier, T.; Martinez-Hoyos, M.; Marin-Amieva, M.; Colmenarejo, G.; Porras-De Francisco, E.; Alvarez-Pedraglio, A. I.; Fraile-Gabaldon, M. T.; Torres-Gomez, P. A.; Lopez-Quezada, L.; Gold, B.; Roberts, J.; Ling, Y.; Somersan-Karakaya, S.; Little, D.; Cammack, N.; Nathan, C.; Mendoza-Losana, A. Identification of Novel Anti-Mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium Tuberculosis. ACS Infectious Diseases 2015, 1 (12), 580–585. https://doi.org/10.1021/acsinfecdis.5b00025.
  8. Gold, B.; Smith, R.; Nguyen, Q.; Roberts, J.; Ling, Y.; Lopez Quezada, L.; Somersan, S.; Warrier, T.; Little, D.; Pingle, M.; Zhang, D.; Ballinger, E.; Zimmerman, M.; Dartois, V.; Hanson, P.; Mitscher, L. A.; Porubsky, P.; Rogers, S.; Schoenen, F. J.; Nathan, C.; Aubé, J. Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium Tuberculosis. Journal of Medicinal Chemistry 2016, 59 (13), 6027–6044. https://doi.org/10.1021/acs.jmedchem.5b01833.
  9. Lopez Quezada, L.; Li, K.; McDonald, S. L.; Nguyen, Q.; Perkowski, A. J.; Pharr, C. W.; Gold, B.; Roberts, J.; McAulay, K.; Saito, K.; Somersan Karakaya, S.; Javidnia, P. E.; Porras de Francisco, E.; Amieva, M. M.; Dı́az, S. P.; Mendoza Losana, A.; Zimmerman, M.; Liang, H.-P. H.; Zhang, J.; Dartois, V.; Sans, S.; Lagrange, S.; Goullieux, L.; Roubert, C.; Nathan, C.; Aubé, J. Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium Tuberculosis. ACS Infectious Diseases 2019, 5 (8), 1433–1445. https://doi.org/10.1021/acsinfecdis.9b00112.
  10. Lopez Quezada, L.; Silve, S.; Kelinske, M.; Liba, A.; Diaz Gonzalez, C.; Kotev, M.; Goullieux, L.; Sans, S.; Roubert, C.; Lagrange, S.; Bacqué, E.; Couturier, C.; Pellet, A.; Blanc, I.; Ferron, M.; Debu, F.; Li, K.; Aubé, J.; Roberts, J.; Little, D.; Ling, Y.; Zhang, J.; Gold, B.; Nathan, C. Bactericidal Disruption of Magnesium Metallostasis in Mycobacterium Tuberculosis Is Counteracted by Mutations in the Metal Ion Transporter CorA. mBio 2019, 10 (4). https://doi.org/10.1128/mBio.01405-19.
  11. Su, H.; Lin, K.; Tiwari, D.; Healy, C.; Trujillo, C.; Liu, Y.; Ioerger, T. R.; Schnappinger, D.; Ehrt, S. Genetic Models of Latent Tuberculosis in Mice Reveal Differential Influence of Adaptive Immunity. Journal of Experimental Medicine 2021, 218 (9). https://doi.org/10.1084/jem.20210332.
  12. Lin, G.; Li, D.; de Carvalho, L. P. S.; Deng, H.; Tao, H.; Vogt, G.; Wu, K.; Schneider, J.; Chidawanyika, T.; Warren, J. D.; Li, H.; Nathan, C. Inhibitors Selective for Mycobacterial versus Human Proteasomes. Nature 2009, 461 (7264), 621–626. https://doi.org/10.1038/nature08357.
  13. Zhang, H.; Hsu, H.-C.; Kahne, S. C.; Hara, R.; Zhan, W.; Jiang, X.; Burns-Huang, K.; Ouellette, T.; Imaeda, T.; Okamoto, R.; Kawasaki, M.; Michino, M.; Wong, T.-T.; Toita, A.; Yukawa, T.; Moraca, F.; Vendome, J.; Saha, P.; Sato, K.; Aso, K.; Ginn, J.; Meinke, P. T.; Foley, M.; Nathan, C. F.; Darwin, K. H.; Li, H.; Lin, G. Macrocyclic Peptides That Selectively Inhibit the Mycobacterium Tuberculosis Proteasome. Journal of Medicinal Chemistry 2021, 64 (9), 6262–6272. https://doi.org/10.1021/acs.jmedchem.1c00296.
  14. Bryk, R.; Arango, N.; Venugopal, A.; Warren, J. D.; Park, Y.-H.; Patel, M. S.; Lima, C. D.; Nathan, C. Triazaspirodimethoxybenzoyls as Selective Inhibitors of Mycobacterial Lipoamide Dehydrogenase,. Biochemistry 2010, 49 (8), 1616–1627. https://doi.org/10.1021/bi9016186.
  15. Ginn, J.; Jiang, X.; Sun, S.; Michino, M.; Huggins, D. J.; Mbambo, Z.; Jansen, R.; Rhee, K. Y.; Arango, N.; Lima, C. D.; Liverton, N.; Imaeda, T.; Okamoto, R.; Kuroita, T.; Aso, K.; Stamford, A.; Foley, M.; Meinke, P. T.; Nathan, C.; Bryk, R. Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions. ACS Infectious Diseases 2021, 7 (2), 435–444. https://doi.org/10.1021/acsinfecdis.0c00788.
  16. Ballinger, E.; Mosior, J.; Hartman, T.; Burns-Huang, K.; Gold, B.; Morris, R.; Goullieux, L.; Blanc, I.; Vaubourgeix, J.; Lagrange, S.; Fraisse, L.; Sans, S.; Couturier, C.; Bacqué, E.; Rhee, K.; Scarry, S. M.; Aubé, J.; Yang, G.; Ouerfelli, O.; Schnappinger, D.; Ioerger, T. R.; Engelhart, C. A.; McConnell, J. A.; McAulay, K.; Fay, A.; Roubert, C.; Sacchettini, J.; Nathan, C. Opposing Reactions in Coenzyme A Metabolism Sensitize Mycobacterium Tuberculosis to Enzyme Inhibition. Science 2019, 363 (6426). https://doi.org/10.1126/science.aau8959.

Rhee lab

Team

  • Kyle Planck
  • Vijay Soni
  • Emma Spady
  • Andrea Tellez

About

In addition to its direct impact on human health, TB is both a transmissible cause and consequence of poverty. Control of the TB pandemic is thus not only critical to eliminating a leading cause of death and disability, but also  remedying a major medical driver of global socioeconomic disparity. Unfortunately, the curative potential of current TB chemotherapies has been stunted by their complexity and toxicity, and more concerning emergence of drug resistance. Simpler, safer cures for TB thus comprise a major area of urgent and unmet societal need.

Role & Expertise

We seek to accelerate TB drug development through the introduction of new concepts and technologies that have made it possible to replace historically empiric aspects of rational drug development with explicit and simultaneous experimental measurements of the intrabacterial pharmacokinetic and pharmacodynamic properties of chemical compounds within viable Mtb bacteria.  

Metabolomic profiling of compound uptake, penetration, accumulation, metabolism, efflux (PK) and activity (PD), and compound-compound interactions

Links

Rhee lab Website

References

  1. Kreutzfeldt KM, Jansen RS, Hartman TE, Gouzy A, Wang R, Krieger IV, Zimmerman MD, Gengenbacher M, Sarathy JP, Xie M, Dartois V, Sacchettini JC, Rhee KY, Schnappinger D, Ehrt S. CinA mediates multidrug tolerance in Mycobacterium tuberculosis. Nat Commun. 2022, 13(1) (2203). https://doi: 10.1038/s41467-022-29832-1.
  2. Rhee KY, Jansen RS, Grundner C. Activity-based annotation: the emergence of systems biochemistry Trends Biochem Sci. 2022 Apr 13:S0968-0004(22)00076-7. https://doi: 10.1016/j.tibs.2022.03.017
  3. Ballinger, E.; Mosior, J.; Hartman, T.; Burns-Huang, K.; Gold, B.; Morris, R.; Goullieux, L.; Blanc, I.; Vaubourgeix, J.; Lagrange, S.; Fraisse, L.; Sans, S.; Couturier, C.; Bacqué, E.; Rhee, K.; Scarry, S. M.; Aubé, J.; Yang, G.; Ouerfelli, O.; Schnappinger, D.; Ioerger, T. R.; Engelhart, C. A.; McConnell, J. A.; McAulay, K.; Fay, A.; Roubert, C.; Sacchettini, J.; Nathan, C. Opposing Reactions in Coenzyme A Metabolism Sensitize Mycobacterium Tuberculosis to Enzyme Inhibition. Science 2019, 363 (6426). https://doi.org/10.1126/science.aau8959.
  4. Wang, Z.; Soni, V.; Marriner, G.; Kaneko, T.; Boshoff, H. I. M.; Barry, C. E.; Rhee, K. Y. Mode-of-Action Profiling Reveals Glutamine Synthetase as a Collateral Metabolic Vulnerability of M. Tuberculosis to Bedaquiline. Proceedings of the National Academy of Sciences of the United States of America 2019, 116 (39). https://doi.org/10.1073/pnas.1907946116.
  5. Chakraborty, S.; Rhee, K. Y. Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm. Cold Spring Harbor Perspectives in Medicine 2015, 5 (8). https://doi.org/10.1101/cshperspect.a021147.
  6. Chakraborty, S.; Gruber, T.; Barry, C. E.; Boshoff, H. I.; Rhee, K. Y. Para-Aminosalicylic Acid Acts as an Alternative Substrate of Folate Metabolism in Mycobacterium Tuberculosis. Science 2013, 339 (6115). https://doi.org/10.1126/science.1228980.
Dirk Schnappinger- Photo by Jörg Meyer (2019)

Schnappinger Lab

Team

Our work depends on close collaborations between the laboratories led by Véronique Dartois (CDI, Hackensack Meridian Health), Sabine Ehrt (Weill Cornell Medical College), Thomas Ioerger (Texas A&M University), Jeremy Rock (Rockefeller University), and Dirk Schnappinger (Weill Cornell Medical College)

  • Rodrigo Aguilera Olvera (WCMC)
  • Arwa Alharbi (WCMC)
  • Arka Banerjee (WCMC)
  • Barbara Bosch (RU)
  • Michael DeJesus (RU)
  • Curtis Engelhart (WCMC)
  • Shipra Grover (WCMC)
  • Heather Kim (WCMC)
  • Shuqi Li (RU)
  • Alan Mason (CDI)
  • Nick Poulton (RU)
  • Jansy Sarathy (CDI)
  • Daniel Sullivan (WCMC)
  • Natalie Thornton (WCMC)
  • Prajna Tripathi (WCMC)
  • Carolina Trujillo (WCMC)
  • Joshua Wallach (WCMC)
  • Matthew Zimmerman (CDI)

Role & Expertise

Our mission is to prioritize new targets for drug development and help defining the mechanisms by which TBDA hits and leads inhibit growth of M. tuberculosis.

Our team combines expertise in genetics & genomics, statistics & bioinformatics, TB animal models and pharmacokinetics.

Links

https://pebble.rockefeller.edu/

https://www.rockefeller.edu/research/160909-laboratory-of-host-pathogen-biology/

https://people.engr.tamu.edu/ioerger/index.html

https://www.ehrtschnappingerlabs.org/

References

  1. Dutta, E.; DeJesus, M. A.; Ruecker, N.; Zaveri, A.; Koh, E. I.; Sassetti, C. M.; Schnappinger, D.; Ioerger, T. R. An Improved Statistical Method to Identify Chemical-Genetic Interactions by Exploiting Concentration-Dependence. PLoS ONE 2021, 16 (10 October). https://doi.org/10.1371/journal.pone.0257911.
  2. Grover, S.; Engelhart, C. A.; Pérez-Herrán, E.; Li, W.; Abrahams, K. A.; Papavinasasundaram, K.; Bean, J. M.; Sassetti, C. M.; Mendoza-Losana, A.; Besra, G. S.; Jackson, M.; Schnappinger, D. Two-Way Regulation of MmpL3 Expression Identifies and Validates Inhibitors of MmpL3 Function in Mycobacterium Tuberculosis. ACS Infectious Diseases2021, 7 (1), 141–152. https://doi.org/10.1021/ACSINFECDIS.0C00675.
  3. Bosch, B.; DeJesus, M. A.; Poulton, N. C.; Zhang, W.; Engelhart, C. A.; Zaveri, A.; Lavalette, S.; Ruecker, N.; Trujillo, C.; Wallach, J. B.; Li, S.; Ehrt, S.; Chait, B. T.; Schnappinger, D.; Rock, J. M. Genome-Wide Gene Expression Tuning Reveals Diverse Vulnerabilities of M. Tuberculosis. Cell 2021, 184 (17), 4579-4592.e24. https://doi.org/10.1016/j.cell.2021.06.033.
  4. Gengenbacher, M.; Zimmerman, M. D.; Sarathy, J. P.; Kaya, F.; Wang, H.; Mina, M.; Carter, C.; Hossen, M. A.; Su, H.; Trujillo, C.; Ehrt, S.; Schnappinger, D.; Dartois, V. Tissue Distribution of Doxycycline in Animal Models of Tuberculosis. Antimicrobial Agents and Chemotherapy 2020, 64 (5). https://doi.org/10.1128/AAC.02479-19.
  5. Beites, T.; O’Brien, K.; Tiwari, D.; Engelhart, C. A.; Walters, S.; Andrews, J.; Yang, H. J.; Sutphen, M. L.; Weiner, D. M.; Dayao, E. K.; Zimmerman, M.; Prideaux, B.; Desai, P. V.; Masquelin, T.; Via, L. E.; Dartois, V.; Boshoff, H. I.; Barry, C. E.; Ehrt, S.; Schnappinger, D. Plasticity of the Mycobacterium Tuberculosis Respiratory Chain and Its Impact on Tuberculosis Drug Development. Nature Communications 2019 10:1 2019, 10 (1), 1–12. https://doi.org/10.1038/s41467-019-12956-2.
  6. Tiwari, D.; Park, S. W.; Essawy, M. M.; Dawadi, S.; Mason, A.; Nandakumar, M.; Zimmerman, M.; Mina, M.; Ho, H. P.; Engelhart, C. A.; Ioerger, T.; Sacchettini, J. C.; Rhee, K.; Ehrt, S.; Aldrich, C. C.; Dartois, V.; Schnappinger, D. Targeting Protein Biotinylation Enhances Tuberculosis Chemotherapy. Science Translational Medicine2018, 10 (438). https://doi.org/10.1126/scitranslmed.aal1803.
  7. Puckett, S.; Trujillo, C.; Wang, Z.; Eoh, H.; Ioerger, T. R.; Krieger, I.; Sacchettini, J.; Schnappinger, D.; Rhee, K. Y.; Ehrt, S. Glyoxylate Detoxification Is an Essential Function of Malate Synthase Required for Carbon Assimilation in Mycobacterium Tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 2017, 114 (11). https://doi.org/10.1073/pnas.1617655114.
  8. Botella, L.; Vaubourgeix, J.; Livny, J.; Schnappinger, D. Depleting Mycobacterium Tuberculosis of the Transcription Termination Factor Rho Causes Pervasive Transcription and Rapid Death. Nature Communications 2017 8:1 2017, 8 (1), 1–10. https://doi.org/10.1038/ncomms14731.
  9. Lin, K.; O’Brien, K. M.; Trujillo, C.; Wang, R.; Wallach, J. B.; Schnappinger, D.; Ehrt, S. Mycobacterium Tuberculosis Thioredoxin Reductase Is Essential for Thiol Redox Homeostasis but Plays a Minor Role in Antioxidant Defense. PLoS Pathogens2016, 12 (6). https://doi.org/10.1371/journal.ppat.1005675.
  10. Kim, J. H.; O’Brien, K. M.; Sharma, R.; Boshoff, H. I. M.; Rehren, G.; Chakraborty, S.; Wallach, J. B.; Monteleone, M.; Wilson, D. J.; Aldrich, C. C.; Barry, C. E.; Rhee, K. Y.; Ehrt, S.; Schnappinger, D. A Genetic Strategy to Identify Targets for the Development of Drugs That Prevent Bacterial Persistence. Proceedings of the National Academy of Sciences of the United States of America 2013, 110 (47). https://doi.org/10.1073/pnas.1315860110.