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)

Gopal P, Dick T. Targeted protein degradation in antibacterial drug discovery?. Prog Biophys Mol Biol. 2020; 152:10-14. PMCID: PMC7145722.

Gopal P, Sarathy JP, Yee M, Ragunathan P, Shin J, Bhushan S, Zhu J, Akopian T, Kandror O, Lim TK, Gengenbacher M, Lin Q, Rubin EJ, Grüber G, Dick T. Pyrazinamide triggers degradation of its target aspartate decarboxylase. Nat Commun. 2020; 11(1):1661. PMCID: PMC7125159.

Li M, Phua ZY, Xi Y, Xu Z, Nyantakyi S, Li W, Jackson M, Wong M, Lam Y, Chng, S-S, Go M-L, Dick T. Potency Increase of Spiroketal Analogs of Membrane Inserting Indolyl Mannich Base Antimycobacterials Is Due to Acquisition of MmpL3 Inhibition. ACS Infectious Diseases 2020, PMID: 32413266.

Sarathy JP, Ganapathy US, Zimmerman MD, Dartois V, Gengenbacher M, Dick T. TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus. Antimicrob Agents Chemother. 2020; 64(4). PMCID: PMC7179298.

Yam YK, Alvarez N, Go ML, Dick T. Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”. Front Microbiol. 2020; 11:359. PMCID: PMC7064438.

Dick T. Rifabutin: A Repurposing Candidate for Mycobacterium abscessus Lung Disease. Front Microbiol. 2020; 11:371. PMCID: PMC7056868.

Aziz DB, Go ML, Dick T. Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41. Antibiotics (Basel). 2020; 9(2). PMCID: PMC7168051.

Sarathy JP, Ragunathan P, Cooper CB, Upton AM, Grüber G, Dick T. TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug’s Uncoupler Activity. Antimicrob Agents Chemother. 2020; 64(2). PMCID: PMC6985740.

Dick T, Shin SJ, Koh WJ, Dartois V, Gengenbacher M. Rifabutin Is Active against Mycobacterium abscessus in Mice. Antimicrob Agents Chemother. 2020; 64(2). PMCID: PMC6985736.

Wong CF,  Lau AM,  Harikishore A,  Saw WG,  Joon S,  Ragunathan P,  Bhushan S,  Fong CS,  Ngan, SK  Bates RW,  Dick T,  Grüber G. A systematic assessment of mycobacterial F1‐ATPase subunit ε’s role in latent ATPase hydrolysis. FEBS J. 2020; https://doi.org/10.1111/febs.15440

Safi H, Sherman DR, Dick T, Alland D. Reply to Vargas and Farhat: Mycobacterium tuberculosis glpK mutants in human tuberculosis. Proc Natl Acad Sci U S A. 2020; 117(8):3913-3914. PMCID: PMC7049110.

Saw WG, Wong CF, Dick T, Grüber G. Overexpression, purification, enzymatic and microscopic characterization of recombinant mycobacterial F-ATP synthase. Biochem Biophys Res Commun. 2020; 522(2):374-380. PMID: 31761325.

Kamariah N, Ragunathan P, Shin J, Saw WG, Wong CF, Dick T, Grüber G. Unique structural and mechanistic properties of mycobacterial F-ATP synthases: Implications for drug design. Prog Biophys Mol Biol. 2020; 152:64-73. PMID: 31743686.

Hotra A, Ragunathan P, Ng PS, Seankongsuk P, Harikishore A, Sarathy JP, Saw WG, Lakshmanan U, Sae-Lao P, Kalia NP, Shin J, Kalyanasundaram R, Anbarasu S, Parthasarathy K, Pradeep CN, Makhija H, Dröge P, Poulsen A, Tan JHL, Pethe K, Dick T, Bates RW, Grüber G. Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines. Angew Chem Int Ed Engl. 2020; PMID: 32337801.

Chong SMS, Manimekalai MSS, Sarathy JP, Williams ZC, Harold LK, Cook GM, Dick T, Pethe K, Bates RW, Grüber G. Antituberculosis Activity of the Antimalaria Cytochrome bcc Oxidase Inhibitor SCR0911. ACS Infect Dis. 2020; 6(4):725-737. PMID: 32092260.

Sarathy JP, Gruber G, Dick T. Re-Understanding the Mechanisms of Action of the Anti-Mycobacterial Drug Bedaquiline. Antibiotics (Basel). 2019; 8(4). PMCID: PMC6963887.

Gopal P, Grüber G, Dartois V, Dick T. Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide. Trends Pharmacol Sci. 2019; 40(12):930-940. PMCID: PMC6884696.

Sarathy JP, Ragunathan P, Shin J, Cooper CB, Upton AM, Grüber G, Dick T. TBAJ-876 Retains Bedaquiline’s Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP Synthase. Antimicrob Agents Chemother. 2019; 63(10). PMCID: PMC6761534.

Lindman M, Dick T. Bedaquiline Eliminates Bactericidal Activity of β-Lactams against Mycobacterium abscessus. Antimicrob Agents Chemother. 2019; 63(8). PMCID: PMC6658768.

Dartois V, Sizemore C, Dick T. Editorial: NTM-The New Uber-Bugs. Front Microbiol. 2019; 10:1299. PMCID: PMC6582698.

Negatu DA, Yamada Y, Xi Y, Go ML, Zimmerman M, Ganapathy U, Dartois V, Gengenbacher M, Dick T. Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in Mycobacterium tuberculosis. mBio. 2019; 10(2). PMCID: PMC6437058.

Ganapathy US, Dartois V, Dick T. Repositioning rifamycins for Mycobacterium abscessus lung disease. Expert Opinion Drug Discov 2019; 14 (9), 867-878. PMCID: PMC6663560

Safi H, Gopal P, Lingaraju S, Ma S, Levine C, Dartois V, Yee M, Li L, Blanc L, Ho Liang HP, Husain S, Hoque M, Soteropoulos P, Rustad T, Sherman DR, Dick T, Alland D. Phase variation in Mycobacterium tuberculosis glpK produces transiently heritable drug tolerance. Proc Natl Acad Sci U S A. 2019; 116(39):19665-19674. PMCID: PMC6765255.

Saw WG, Wu ML, Ragunathan P, Biuković G, Lau AM, Shin J, Harikishore A, Cheung CY, Hards K, Sarathy JP, Bates RW, Cook GM, Dick T, Grüber G. Disrupting coupling within mycobacterial F-ATP synthases subunit ε causes dysregulated energy production and cell wall biosynthesis. Sci Rep. 2019, 14; 9(1):16759. PMCID: PMC6856130.

Williams JT, Haiderer ER, Coulson GB, Conner KN, Ellsworth E, Chen C, Alvarez-Cabrera N, Li W, Jackson M, Dick T, Abramovitch RB. Identification of New MmpL3 Inhibitors by Untargeted and Targeted Mutant Screens Defines MmpL3 Domains with Differential Resistance. Antimicrob Agents Chemother. 2019; 63(10). PMCID: PMC6761494.

Zhong W, Pasunooti KK, Balamkundu S, Wong YH, Nah Q, Gadi V, Gnanakalai S, Chionh YH, McBee ME, Gopal P, Lim SH, Olivier N, Buurman ET, Dick T, Liu CF, Lescar J, Dedon PC. Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism. J Med Chem. 2019; 62(17):7788-7805. PMCID: PMC6748665.

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, Zelazny AM. Advancing Translational Science for Pulmonary Nontuberculous Mycobacterial Infections. A Road Map for Research. Am J Respir Crit Care Med. 2019; 199(8):947-951. PMCID: PMC6467310.

Shetty A, Dick T. Mycobacterial Cell Wall Synthesis Inhibitors Cause Lethal ATP Burst. Front Microbiol. 2018; 9:1898. PMCID: PMC6104191.

Wu ML, Aziz DB, Dartois V, Dick T. NTM drug discovery: status, gaps and the way forward. Drug Discov Today. 2018; 23(8):1502-1519. PMCID: PMC6078814.

Aziz DB, Teo JWP, Dartois V, Dick T. Teicoplanin – Tigecycline Combination Shows Synergy Against Mycobacterium abscessus. Front Microbiol. 2018; 9:932. PMCID: PMC5958212.

Negatu DA, Liu JJJ, Zimmerman M, Kaya F, Dartois V, Aldrich CC, Gengenbacher M, Dick T. Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular. Antimicrob Agents Chemother. 2018; 62(3). PMCID: PMC5826148.

Dick T, Dartois V. TB drug susceptibility is more than MIC. Nat Microbiol. 2018; 3(9):971-972. PubMed PMID: 30143801.

Shetty A, Xu Z, Lakshmanan U, Hill J, Choong ML, Chng SS, Yamada Y, Poulsen A, Dick T, Gengenbacher M. Novel Acetamide Indirectly Targets Mycobacterial Transporter MmpL3 by Proton Motive Force Disruption. Front Microbiol. 2018; 9:2960. PMCID: PMC6289072.

Bogdanović N, Sundararaman L, Kamariah N, Tyagi A, Bhushan S, Ragunathan P, Shin J, Dick T, Grüber G. Structure and function of Mycobacterium-specific components of F-ATP synthase subunits α and ε. J Struct Biol. 2018; 204(3):420-434. PMID: 30342092.

Blanc L, Sarathy JP, Alvarez Cabrera N, O’Brien P, Dias-Freedman I, Mina M, Sacchettini J, Savic RM, Gengenbacher M, Podell BK, Prideaux B, Ioerger T, Dick T, Dartois V. Impact of immunopathology on the antituberculous activity of pyrazinamide. J Exp Med. 2018; 215(8):1975-1986. PMCID: PMC6080910.

Chen H, Nyantakyi SA, Li M, Gopal P, Aziz DB, Yang T, Moreira W, Gengenbacher M, Dick T, Go ML. The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs. Front Microbiol. 2018; 9:1627. PMCID: PMC6060259.

Nyantakyi SA, Li M, Gopal P, Zimmerman M, Dartois V, Gengenbacher M, Dick T, Go ML. Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity. J Med Chem. 2018; 61(13):5733-5750. PMCID: PMC6043372.

Chen C, Gardete S, Jansen RS, Shetty A, Dick T, Rhee KY, Dartois V. Verapamil Targets Membrane Energetics in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2018; 62(5). PMCID: PMC5923092.

Joon S, Ragunathan P, Sundararaman L, Nartey W, Kundu S, Manimekalai MSS, Bogdanović N, Dick T, Grüber G. The NMR solution structure of Mycobacterium tuberculosis F-ATP synthase subunit ε provides new insight into energy coupling inside the rotary engine. FEBS J. 2018; 285(6):1111-1128. PMID: 29360236.

Yang X, Wedajo W, Yamada Y, Dahlroth SL, Neo JJ, Dick T, Chui WK. 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. 2018; 144:262-276. PMID: 29274493.

Mukherjee D, Wu ML, Teo JWP, Dick T. Vancomycin and Clarithromycin Show Synergy against Mycobacterium abscessus In Vitro. Antimicrob Agents Chemother. 2017; 61(12). PMCID: PMC5700366.

Gopal P, Nartey W, Ragunathan P, Sarathy J, Kaya F, Yee M, Setzer C, Manimekalai MSS, Dartois V, Grüber G, Dick T. Pyrazinoic Acid Inhibits Mycobacterial Coenzyme A Biosynthesis by Binding to Aspartate Decarboxylase PanD. ACS Infect Dis. 2017; 3(11):807-819. PMCID: PMC5734868.

Low JL, Wu ML, Aziz DB, Laleu B, Dick T. Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates. Front Microbiol. 2017; 8:1539. PMCID: PMC5559473.

Yee M, Klinzing D, Wei JR, Gengenbacher M, Rubin EJ, Chien JY, Hsueh PR, Dick T. Draft Genome Sequence of Mycobacterium avium 11. Genome Announc. 2017; 5(32). PMCID: PMC5552987.

Gopal P, Tasneen R, Yee M, Lanoix JP, Sarathy J, Rasic G, Li L, Dartois V, Nuermberger E, Dick T. In Vivo-Selected Pyrazinoic Acid-Resistant Mycobacterium tuberculosis Strains Harbor Missense Mutations in the Aspartate Decarboxylase PanD and the Unfoldase ClpC1. ACS Infect Dis. 2017; 3(7):492-501. PMCID: PMC5514395.

Aziz DB, Low JL, Wu ML, Gengenbacher M, Teo JWP, Dartois V, Dick T. Rifabutin Is Active against Mycobacterium abscessus Complex. Antimicrob Agents Chemother. 2017;61(6). PMCID: PMC5444174.

Yee M, Klinzing D, Wei JR, Gengenbacher M, Rubin EJ, Dick T. Draft Genome Sequence of Mycobacterium abscessus Bamboo. Genome Announc. 2017; 5(20). PMCID: PMC5477336.

Moreira W, Santhanakrishnan S, Ngan GJY, Low CB, Sangthongpitag K, Poulsen A, Dymock BW, Dick T. Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome. Antimicrob Agents Chemother. 2017; 61(5). PMCID: PMC5404560.

Moreira W, Santhanakrishnan S, Dymock BW, Dick T. Bortezomib Warhead-Switch Confers Dual Activity against Mycobacterial Caseinolytic Protease and Proteasome and Selectivity against Human Proteasome. Front Microbiol. 2017; 8:746. PMCID: PMC5406460.

Yang T, Moreira W, Nyantakyi SA, Chen H, Aziz DB, Go ML, Dick T. Amphiphilic Indole Derivatives as Antimycobacterial Agents: Structure-Activity Relationships and Membrane Targeting Properties. J Med Chem. 2017; 60(7):2745-2763. PMID: 28290692.

Yamada Y, Dick T. Mycobacterial Caseinolytic Protease Gene Regulator ClgR Is a Substrate of Caseinolytic Protease. mSphere. 2017; 2(2). PMCID: PMC5352834.

Yee M, Gopal P, Dick T. Missense Mutations in the Unfoldase ClpC1 of the Caseinolytic Protease Complex Are Associated with Pyrazinamide Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017; 61(2). PMCID: PMC5278685.

Ragunathan P, Sielaff H, Sundararaman L, Biuković G, Subramanian Manimekalai MS, Singh D, Kundu S, Wohland T, Frasch W, Dick T, Grüber G. The uniqueness of subunit α of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation. J Biol Chem. 2017; 292(27):11262-11279. PMCID: PMC5500794.

Li M, Nyantakyi SA, Gopal P, Aziz DB, Dick T, Go ML. Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents. ACS Med Chem Lett. 2017; 8(11):1165-1170. PMCID: PMC5683698.

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.