Our Labs

The lab’s focus is on the discovery of new preclinical development compounds against TB and Non-Tuberculous Mycobacterial (NTM) lung disease, including Mycobacterium abscessus and Mycobacterium avium. We apply a ‘compound first strategy’, i.e. we start with new chemical entities showing whole cell activity. This is followed by target deconvolution and hit-to-lead chemistry to deliver target-lead couples. In addition to de novo drug discovery, we carry our repositioning projects. Overall, we are prioritizing broad spectrum anti-mycobacterials active against both NTM and TB. NTM lung disease is depicted in Fig. 1. Fig. 2 shows a flow chart guiding compound progression. Fig. 3 shows a recent example of target deconvolution.  

Figure 1 Lung disease caused by Mycobacterium abscessus. Smooth and rough colonies of the opportunistic pathogen are shown at the bottom.

Figure 2 Flow chart for guiding the discovery of new NTM antibiotics. The flow chart for the discovery of new drugs active against Mycobacterium tuberculosis is similar. Wu et al. (2018) Drug Discovery Today, doi: 10.1016/j.drudis.2018.04.001.F

Figure 3 Recent target deconvolution project for a new antibiotic class (indole propionic acid, IPA) active against TB and NTM. Negatu et al. (2019) mBio, DOI: 10.1128/mBio.02781-18.

Recent publications (since 2017)

Ganapathy U., Dartois V., and Dick T. (2019) Repositioning rifamycins for Mycobacterium abscessus lung disease. Expert Opinion on Drug Discovery. Expert Opinion on Drug Discovery, DOI: 10.1080/17460441.2019.1629414.

Lindman M. and Dick T. (2019) Bedaquiline eliminates bactericidal activity of imipenem and cefoxitin against Mycobacterium abscessus. Antimicrobial Agents Chemotherapy DOI: 10.1128/AAC.00827-19.

V Dartois, C Sizemore, T Dick (2019) NTM: the new uber bugs Front. Microbiol.

Negatu DA, Yamada Y, Xi Y, Go ML, Zimmerman M, Ganapathy U, Dartois V, Martin Gengenbacher M, and Dick T. (2019) Gut microbiota metabolite indole propionic acid targets tryptophan biosynthesis in Mycobacterium tuberculosis. mBio, DOI: 10.1128/mBio.02781-18.

Dick T and Dartois V (2018) TB drug susceptibility is more than MIC. Nature Microbiology 3, 971–972

Daniel-Wayman S, Abate G, Barber DL, Bermudez LE, Coler RN, Cynamon MH, Daley CL , Davidson RM, Dick T, Floto RA, Henkle E, Holland SM, Jackson M, Lee RE , Nuermberger EL, Olivier KN, Ordway DJ, Prevots DR , Sacchettini JC, Salfinger M, Sassetti CM, Sizemore CF, Winthrop KL , and Zelazny AM (2018) Advancing Translational Science for Pulmonary NTM Infections: A Roadmap for Research. American Journal of Respiratory and Critical Care Medicine.  doi.org/10.1164/rccm.201807-1273PP

Chen H, Nyantakyi SA, Li M, Gopal P, Aziz DB, Yang T, Moreira W, Gengenbacher M, Dick T, Go ML (2018) The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs. Frontiers in Microbiology doi: 10.3389/fmicb.2018.01627

Wu M.L., Aziz D.B., Dartois V., and Dick T. (2018) NTM drug discovery: status, gaps and the way forward. Drug Discovery Today. doi.org/10.1016/j.drudis.2018.04.001.

Bogdanović N, Sundararaman L, Kamariah N, Tyagi A, Bhushan S, Ragunathan P, Shin J, Dick T and Grüber G (2018) Structure and function of Mycobacterium-specific components of F-ATP synthase subunits α and ε Journal of Structural Biology. doi.org/10.1016/j.jsb.2018.10.006

Nyantakyi SA, Li M, Gopal P, Zimmerman M, Dartois V, Gengenbacher M, Dick T, Go ML (2018) Indolyl Azaspiroketal Mannich Bases Are Potent Anti-mycobacterial Agents with Selective Membrane Permeabilizing Effects and In Vivo Activity. Journal of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00777

Shetty A, Xu Z, Lakshmanan U, Hill J, Choong ML, Chng SS, Yamada Y, Poulsen A, Dick T, Gengenbacher M (2018) Novel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruption. Frontiers in Microbiology 9, 2960

Shetty A. and Dick T. (2018) Mycobacterial cell wall synthesis inhibitors cause lethal ATP burst. Frontiers in Microbiology. doi: 10.3389/fmicb.2018.01898.

Blanc L., Sarathy J., Cabrera N.A., O’Brien P., Dias-Freedman I., Mina M., Sacchettini J., Savic R., Gengenbacher M., Podell B.K., Prideaux B., Ioerger T., Dick T., and Dartois V. (2018) Impact of immunopathology on the antituberculous activity of pyrazinamide. Journal of Experimental Medicine.http://doi.org/10.1084/jem.20180518

Aziz D.B., Teo J.W.P., Dartois V., Dick T. (2018) Teicoplanin – tigecycline combination shows synergy against Mycobacterium abscessus. Frontiers in Microbiology. doi: 10.3389/fmicb.2018.00932.

Chen C, Gardete S, Jansen RS, Shetty A, Dick T, Rhee KY, Dartois V (2018) Verapamil targets membrane energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother. PMI: 29463541

Yang X, Wedajo W, Yamada Y, Dahlroth SL, Neo JJ, Dick T, Chui WK (2018) 1,3,5-triazaspiro[5.5]undeca-2,4-dienes as selective Mycobacterium tuberculosis dihydrofolate reductase inhibitors with potent whole cell activity. Eur J Med Chem 144: 262-276. PMI: 29274493

Joon S, Ragunathan P, Sundararaman L, Nartey W, Kundu S, Manimekalai MSS, Bogdanovic N, Dick T, Gruber G (2018) The NMR solution structure of Mycobacterium tuberculosis F-ATP synthase subunit epsilon provides new insight into energy coupling inside the rotary engine. FEBS J. PMI: 29360236

Negatu DA, Liu JJJ, Zimmerman M, Kaya F, Dartois V, Aldrich CC, Gengenbacher M, Dick T (2018) Whole cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular. Antimicrob Agents Chemother. PMI: 29229639

TBAJ-876 retains Bedaquiline’s activity against subunit c and ϵ of Mycobacterium tuberculosis F-ATP synthase. JP Sarathy, P Ragunathan, S Joon, CB Cooper, AM Upton, G Grüber, T Dick (2019). Antimicrobial Agents and Chemotherapy AAC.01191-19; DOI: 10.1128/AAC.01191-19

Li M, Nyantakyi SA, Gopal P, Aziz DB, Dick T, Go ML (2017) Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents. ACS Med Chem Lett 8: 1165-1170. PMI: 29152049

Aziz D.B., Low J.L., Wu M.L., Gengenbacher M., Teo J.W.P., Dartois V. and Dick T. (2017) Rifabutin is active against Mycobacterium abscessus complex. Antimicrobial Agents Chemotherapy. doi:10.1128/AAC.00155-17.

Low J.L., Wu M.L., Aziz D.B., Laleu B., Dick T. (2017) Screening of TB actives for activity against nontuberculous mycobacteria delivers high hit rates. PMID: 28861054

Mukherjee D., Teo J.W.P. and Dick T. (2017) In vitro combination of vancomycin and clarithromycin shows synergy against Mycobacterium abscessus isolates.  doi: 10.1128/AAC.01298-17

Yang T., Moreira W., Chen H., Nyantaki S., Aziz D.B., Go M.L. and Dick T. (2017) Amphiphilic indole derivatives as anti-mycobacterial agents: structure-activity relationships and membrane targeting properties. Journal Medicinal Chemistry. Doi: 10.1021acs.jmedchem.6b01530.

Yee M., Klinzing D., Wei J-R., Gengenbacher M., Rubin E.J., and Dick T. (2017) Draft genome sequence of Mycobacterium abscessus Bamboo. Genome Announcements. DOI:10.1128/genomeA.00388-17

Yee M., Klinzing D., Wei J-R., Gengenbacher M., Rubin E.J., Chien J-Y., Hsueh P-R. and Dick T. (2017) Draft genome sequence of Mycobacterium avium 11. Genome Announcements. DOI:10.1128/genomeA.00766-17.

Gopal P., Nartey W., Ragunathan P., Sarathy J., Kaya F., Yee M., Setzer C., Dartois V., Grüber G. and Dick T. (2017) Pyrazinoic acid inhibits mycobacterial coenzyme A biosynthesis by binding to aspartate decarboxylase PanD. ACS Infect. Dis., 2017, 3 (11), pp 807–819, DOI: 10.1021/acsinfecdis.7b00079

Gopal P., Tasneen R., Yee M., Lanoix J.-P., Sarathy J., Rasic G., Li L., Dartois V., Nuermberger E. and Dick T. (2017) In vivo selected pyrazinoic acid resistant M. tuberculosis strains harbour missense mutations in the aspartate decarboxylase PanD and unfoldase ClpC1. ACS Infectious Diseases. doi: 10.1021/acsinfecdis.7b00017.

Yee M., Gopal P., Dick T. (2017) Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis. Antimicrobial Agents Chemotherapy 61. PMI: 27872068

Moreira W, Santhanakrishnan S., Ngan G.J.Y., Low C.B., Sangthongpitag K., Poulsen A., Dymock B.W. and Dick T. (2017) Towards selective mycobacterial ClpP1P2 inhibitors with reduced activity against the human proteasome. Antimicrobial Agents Chemotherapy. doi:10.1128/AAC.02307-16.

Moreira W., Santhanakrishnan S., Dymock B.W. and Dick T. (2017) Bortezomib warhead-switch confers dual activity against mycobacterial caseinolytic protease and proteasome and selectivity against human proteasome. Frontiers in Microbiology doi: 10.3389/fmicb.2017.00746.

Yamada Y. and Dick T. (2017) The mycobacterial caseinolytic protease gene regulator ClgR is substrate of caseinolytic protease. mSphere doi.org/10.1128/mSphere.00338-16.

Ragunathan P., Sielaff H., Sundararaman L., Biukovic G., Manimekalai M.S.S., Singh D., Kundu S., Wohland T., Frasch W., Dick T. and Grüber G. (2017) The uniqueness of subunit α of mycobacterial F- ATP synthases: An evolutionary variant for niche adaptation. Journal of Biological Chemistry. doi: 10.1074/jbc.M117.784959.

M.L. Wu, T. Dick, G. Grueber. Unravelling The Essentials Of Subunit ε Of Mycobacterial F-ATP Synthases For Proper Cell Growth Of The Pathogen And Novel Inhibitors Of Mycobacterial F-ATP Synthases. Singapore patent application No.: 10201807627U; September 5, 2018.

Grueber, R. Roderick, A. Hotra, T. Dick, K. Pethe. Compounds for Treating Tuberculosis. WO 2018/151681 A1; August 23, 2018.

Grueber, R.W. Bates;

News from the TB and NTM drug discovery laboratory

Characterizing the mechanism of action of the TB drug pyrazinamide (PZA), we discovered that this critical first line drug does not act as an inhibitor of its target aspartate decarboxylase PanD. Rather, binding of the drug to PanD promotes degradation of the protein via the caseinolytic protease complex. Thus, PZA acts as target degrader: the drug makes Mycobacterium tuberculosis ‘eat up’ one of its essential enzymes. Gopal et al. unpublished. POA: PZA is a prodrug. Pyrazinoic acid (POA) is the bioactive component of PZA.