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 (2020/2022)

Negatu DA, Zimmerman MD, Dartois V, Dick T. Strongly Bactericidal All-Oral β-Lactam Combinations for the Treatment of Mycobacterium abscessus Lung Disease. Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0079022. doi: 10.1128/aac.00790-22. Epub 2022 Sep 1. PMID: 36047786; PMCID: PMC9487536.

Lan T, Ganapathy US, Sharma S, Ahn YM, Zimmerman M, Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois V, Freundlich JS, Dick T, Aldrich CC. Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance. Angew Chem Int Ed Engl. 2022 Nov 7;61(45):e202211498. doi: 10.1002/anie.202211498. Epub 2022 Oct 12. PMID: 36222275; PMCID: PMC9633546.

Sarathy JP, Zimmerman MD, Gengenbacher M, Dartois V, Dick T. Mycobacterium tuberculosis DprE1 Inhibitor OPC-167832 Is Active against Mycobacterium abscessus In Vitro. Antimicrob Agents Chemother. 2022 Nov 9:e0123722. doi: 10.1128/aac.01237-22. Epub ahead of print. PMID: 36350151.

Ganapathy US, Dick T. Why Matter Matters: Fast-Tracking Mycobacterium abscessus Drug Discovery. Molecules. 2022 Oct 17;27(20):6948. doi: 10.3390/molecules27206948. PMID: 36296540; PMCID: PMC9608607.

Madani A, Negatu DA, El Marrouni A, Miller RR, Boyce CW, Murgolo N, Bungard CJ, Zimmerman MD, Dartois V, Gengenbacher M, Olsen DB, Dick T. Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus. Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0066922. doi: 10.1128/aac.00669-22. Epub 2022 Aug 25. PMID: 36005813; PMCID: PMC9487482.

Hegde PV, Aragaw WW, Cole MS, Jachak G, Ragunathan P, Sharma S, Harikishore A, Grüber G, Dick T, Aldrich CC. Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents. Bioorg Med Chem. 2022 Nov 15;74:117046. doi: 10.1016/j.bmc.2022.117046. Epub 2022 Oct 7. PMID: 36228522.

Li M, Yamada Y, Rodriguez GM, Dick T, Go ML. Redox Cycling Dioxonaphthoimidazoliums Disrupt Iron Homeostasis in Mycobacterium bovis Bacillus Calmette-Guérin. Microbiol Spectr. 2022 Nov 15:e0197022. doi: 10.1128/spectrum.01970-22. Epub ahead of print. PMID: 36377959.

Mann L, Ganapathy US, Abdelaziz R, Lang M, Zimmerman MD, Dartois V, Dick T, Richter A. In Vitro Profiling of the Synthetic RNA Polymerase Inhibitor MMV688845 against Mycobacterium abscessus. Microbiol Spectr. 2022 Nov 15:e0276022. doi: 10.1128/spectrum.02760-22. Epub ahead of print. PMID: 36377951.

Girardini M, Ferlenghi F, Annunziato G, Degiacomi G, Papotti B, Marchi C, Sammartino JC, Rasheed SS, Contini A, Pasca MR, Vacondio F, Evans JC, Dick T, Müller R, Costantino G, Pieroni M. Expanding the knowledge around antitubercular 5-(2-aminothiazol-4-yl)isoxazole-3-carboxamides: Hit-to-lead optimization and release of a novel antitubercular chemotype via scaffold derivatization. Eur J Med Chem. 2023 Jan 5;245(Pt 2):114916. doi: 10.1016/j.ejmech.2022.114916. Epub 2022 Nov 11. PMID: 36399878.

Wong CF, Saw WG, Basak S, Sano M, Ueno H, Kerk HW, Litty D, Ragunathan P, Dick T, Müller V, Noji H, Grüber G. Structural Elements Involved in ATP Hydrolysis Inhibition and ATP Synthesis of Tuberculosis and Nontuberculous Mycobacterial F-ATP Synthase Decipher New Targets for Inhibitors. Antimicrob Agents Chemother. 2022 Nov 29:e0105622. doi: 10.1128/aac.01056-22. Epub ahead of print. PMID: 36445139.

Dartois V, Dick T. Drug development challenges in nontuberculous mycobacterial lung disease: TB to the rescue. J Exp Med. 2022 Jun 6;219(6). doi: 10.1084/jem.20220445. Epub 2022 May 11. PubMed PMID: 35543723.

Kaya F, Ernest JP, LoMauro K, Gengenbacher M, Madani A, Aragaw WW, Zimmerman MD, Sarathy JP, Alvarez N, Daudelin I, Wang H, Lanni F, Weiner DM, Via LE, Barry CE 3rd, Olivier KN, Dick T, Podell BK, Savic RM, Dartois V. A Rabbit Model to Study Antibiotic Penetration at the Site of Infection for Nontuberculous Mycobacterial Lung Disease: Macrolide Case Study. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0221221. doi: 10.1128/aac.02212-21. Epub 2022 Jan 31. PubMed PMID: 35099272; PubMed Central PMCID: PMC8923217.

Beuchel A, Robaa D, Negatu DA, Madani A, Alvarez N, Zimmerman MD, Richter A, Mann L, Hoenke S, Csuk R, Dick T, Imming P. Structure-Activity Relationship of Anti-Mycobacterium abscessus Piperidine-4-carboxamides, a New Class of NBTI DNA Gyrase Inhibitors. ACS Med Chem Lett. 2022 Mar 10;13(3):417-427. doi: 10.1021/acsmedchemlett.1c00549. eCollection 2022 Mar 10. PubMed PMID: 35300094; PubMed Central PMCID: PMC8919391.

Aragaw WW, Cotroneo N, Stokes S, Pucci M, Critchley I, Gengenbacher M, Dick T. In Vitro Resistance against DNA Gyrase Inhibitor SPR719 in Mycobacterium avium and Mycobacterium abscessus. Microbiol Spectr. 2022 Feb 23;10(1):e0132121. doi: 10.1128/spectrum.01321-21. Epub 2022 Jan 12. PubMed PMID: 35019671; PubMed Central PMCID: PMC8754139.

Saw WG, Leow CY, Harikishore A, Shin J, Cole MS, Aragaw WW, Ragunathan P, Hegde P, Aldrich CC, Dick T, Grüber G. Structural and Mechanistic Insights into Mycobacterium abscessus Aspartate Decarboxylase PanD and a Pyrazinoic Acid-Derived Inhibitor. ACS Infectious Diseases. 2022 Jun 22.

Joon S, Harikishore A, Wong CF, Ragunathan P, Dick T, Grüber G. Atomic solution structure of Mycobacterium abscessus F‐ATP synthase subunit ε and identification of Ep1 Mab F1 as a targeted inhibitor. The FEBS Journal. 2022 May 25.

Ragunathan P, Dick T, Grüber G. Anti-Mycobacterium abscessus Activity of Tuberculosis F-ATP Synthase Inhibitor GaMF1. Antimicrobial Agents and Chemotherapy. 2022 Apr 28;66(5):e00018-22.

Harikishore A, Saw WG, Ragunathan P, Litty D, Dick T, Müller V, Grüber G. Mutational Analysis of Mycobacterial F-ATP Synthase Subunit δ Leads to a Potent δ Enzyme Inhibitor. ACS chemical biology. 2022 Feb 11;17(3):529-35.

Ganapathy US, Del Río RG, Cacho-Izquierdo M, Ortega F, Lelièvre J, Barros-Aguirre D, Aragaw WW, Zimmerman MD, Lindman M, Dartois V, Gengenbacher M, Dick T. A Mycobacterium tuberculosis NBTI DNA Gyrase Inhibitor Is Active against Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Nov 17;65(12):e0151421. doi: 10.1128/AAC.01514-21. Epub 2021 Oct 4. PubMed PMID: 34606340; PubMed Central PMCID: PMC8597734.

Fridianto KT, Li M, Hards K, Negatu DA, Cook GM, Dick T, Lam Y, Go ML. Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis. J Med Chem. 2021 Nov 11;64(21):15991-16007. doi: 10.1021/acs.jmedchem.1c01383. Epub 2021 Oct 27. PubMed PMID: 34706190; PubMed Central PMCID: PMC8595825.

Aragaw WW, Roubert C, Fontaine E, Lagrange S, Zimmerman MD, Dartois V, Gengenbacher M, Dick T. Cyclohexyl-griselimycin is active against Mycobacterium abscessus in mice. Antimicrob Agents Chemother. 2021 Nov 1;:AAC0140021. doi: 10.1128/AAC.01400-21. [Epub ahead of print] PubMed PMID: 34723632.

Remm S, Earp JC, Dick T, Dartois V, Seeger MA. Critical discussion on drug efflux in Mycobacterium tuberculosis. FEMS Microbiol Rev. 2021 Oct 12;. doi: 10.1093/femsre/fuab050. [Epub ahead of print] PubMed PMID: 34637511.

Ganapathy US, Gengenbacher M, Dick T. Epetraborole Is Active against Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0115621. doi: 10.1128/AAC.01156-21. Epub 2021 Jul 19. PubMed PMID: 34280020; PubMed Central PMCID: PMC8448144.

Dartois V, Dick T. A Ginger Root or Plum Model for the Tuberculosis “Granuloma”?. Am J Respir Crit Care Med. 2021 Sep 1;204(5):505-507. doi: 10.1164/rccm.202104-1052ED. PubMed PMID: 34153207; PubMed Central PMCID: PMC8491260.

Ganapathy US, Lan T, Krastel P, Lindman M, Zimmerman MD, Ho H, Sarathy JP, Evans JC, Dartois V, Aldrich CC, Dick T. Blocking Bacterial Naphthohydroquinone Oxidation and ADP-Ribosylation Improves Activity of Rifamycins against Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Aug 17;65(9):e0097821. doi: 10.1128/AAC.00978-21. Epub 2021 Aug 17. PubMed PMID: 34228543; PubMed Central PMCID: PMC8370238.

Negatu DA, Beuchel A, Madani A, Alvarez N, Chen C, Aragaw WW, Zimmerman MD, Laleu B, Gengenbacher M, Dartois V, Imming P, Dick T. Piperidine-4-Carboxamides Target DNA Gyrase in Mycobacterium abscessus. Antimicrob Agents Chemother. 2021 Jul 16;65(8):e0067621. doi: 10.1128/AAC.00676-21. Epub 2021 Jul 16. PubMed PMID: 34001512; PubMed Central PMCID: PMC8284461.

Hegde P, Boshoff HIM, Rusman Y, Aragaw WW, Salomon CE, Dick T, Aldrich CC. Reinvestigation of the structure-activity relationships of isoniazid. Tuberculosis (Edinb). 2021 Jul;129:102100. doi: 10.1016/j.tube.2021.102100. Epub 2021 Jun 5. PubMed PMID: 34116482; PubMed Central PMCID: PMC8324568.

Aragaw WW, Lee BM, Yang X, Zimmerman MD, Gengenbacher M, Dartois V, Chui WK, Jackson CJ, Dick T. Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multienzyme F420H2-dependent reduction. Proc Natl Acad Sci U S A. 2021 Jun 22;118(25). doi: 10.1073/pnas.2025172118. PubMed PMID: 34161270; PubMed Central PMCID: PMC8237569.

Ragunathan P, Cole M, Latka C, Aragaw WW, Hegde P, Shin J, Subramanian Manimekalai MS, Rishikesan S, Aldrich CC, Dick T, Grüber G. Mycobacterium tuberculosis PanD Structure-Function Analysis and Identification of a Potent Pyrazinoic Acid-Derived Enzyme Inhibitor. ACS Chem Biol. 2021 Jun 18;16(6):1030-1039. doi: 10.1021/acschembio.1c00131. Epub 2021 May 13. PubMed PMID: 33984234; PubMed Central PMCID: PMC8217388.

Tan YJ, Li M, Gunawan GA, Nyantakyi SA, Dick T, Go ML, Lam Y. Amide-Amine Replacement in Indole-2-carboxamides Yields Potent Mycobactericidal Agents with Improved Water Solubility. ACS Med Chem Lett. 2021 May 13;12(5):704-712. doi: 10.1021/acsmedchemlett.0c00588. eCollection 2021 May 13. PubMed PMID: 34055215; PubMed Central PMCID: PMC8155280.

Ganapathy US, Del Rio RG, Cacho-Izquierdo M, Ortega F, Lelièvre J, Barros-Aguirre D, Lindman M, Dartois V, Gengenbacher M, Dick T. A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Anti-Mycobacterial Activity. Antimicrob Agents Chemother. 2021 Feb 8;. doi: 10.1128/AAC.02420-20. [Epub ahead of print] PubMed PMID: 33558292; PubMed Central PMCID: PMC8092876.

Wong CF, Lau AM, Harikishore A, Saw WG, Shin J, Ragunathan P, Bhushan S, Ngan SC, Sze SK, Bates RW, Dick T, Grüber G. A systematic assessment of mycobacterial F1 -ATPase subunit ε’s role in latent ATPase hydrolysis. FEBS J. 2021 Feb;288(3):818-836. doi: 10.1111/febs.15440. Epub 2020 Jul 4. PubMed PMID: 32525613.

Li M, Nyantakyi SA, Go ML, Dick T. Resistance against Membrane-Inserting MmpL3 Inhibitor through Upregulation of MmpL5 in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2020 Nov 17;64(12). doi: 10.1128/AAC.01100-20. Print 2020 Nov 17. PubMed PMID: 32958714; PubMed Central PMCID: PMC7674061.

Negatu DA, Gengenbacher M, Dartois V, Dick T. Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties. Front Microbiol. 2020;11:575586. doi: 10.3389/fmicb.2020.575586. eCollection 2020. Review. PubMed PMID: 33193190; PubMed Central PMCID: PMC7652848.

Brzostek J, Fatin A, Chua WH, Tan HY, Dick T, Gascoigne NRJ. Single Cell Analysis of Drug Susceptibility of Mycobacterium Abscessus During Macrophage Infection. Antibiotics (Basel). 2020 Oct 17;9(10). doi: 10.3390/antibiotics9100711. PubMed PMID: 33080864; PubMed Central PMCID: PMC7650608.

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 Aug 3;59(32):13295-13304. doi: 10.1002/anie.202002546. Epub 2020 May 26. PubMed PMID: 32337801.

Li M, Phua ZY, Xi Y, Xu Z, Nyantakyi SA, Li W, Jackson M, Wong MW, Lam Y, Chng SS, Go ML, Dick T. Potency Increase of Spiroketal Analogs of Membrane Inserting Indolyl Mannich Base Antimycobacterials Is Due to Acquisition of MmpL3 Inhibition. ACS Infect Dis. 2020 Jul 10;6(7):1882-1893. doi: 10.1021/acsinfecdis.0c00121. Epub 2020 May 29. PubMed PMID: 32413266; PubMed Central PMCID: PMC7875313.

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 May;152:64-73. doi: 10.1016/j.pbiomolbio.2019.11.006. Epub 2019 Nov 16. Review. PubMed PMID: 31743686.

Gopal P, Dick T. Targeted protein degradation in antibacterial drug discovery?. Prog Biophys Mol Biol. 2020 May;152:10-14. doi: 10.1016/j.pbiomolbio.2019.11.005. Epub 2019 Nov 16. Review. PubMed PMID: 31738980; PubMed Central PMCID: PMC7145722.

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 Apr 10;6(4):725-737. doi: 10.1021/acsinfecdis.9b00408. Epub 2020 Mar 5. PubMed PMID: 32092260.

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 Apr 3;11(1):1661. doi: 10.1038/s41467-020-15516-1. PubMed PMID: 32245967; PubMed Central PMCID: PMC7125159.

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 Mar 24;64(4). doi: 10.1128/AAC.02404-19. Print 2020 Mar 24. PubMed PMID: 31964791; PubMed Central PMCID: PMC7179298.

Yam YK, Alvarez N, Go ML, Dick T. Extreme Drug Tolerance of Mycobacterium abscessus “Persisters”. Front Microbiol. 2020;11:359. doi: 10.3389/fmicb.2020.00359. eCollection 2020. PubMed PMID: 32194537; PubMed Central PMCID: PMC7064438.

Dick T. Rifabutin: A Repurposing Candidate for Mycobacterium abscessus Lung Disease. Front Microbiol. 2020;11:371. doi: 10.3389/fmicb.2020.00371. eCollection 2020. PubMed PMID: 32174907; PubMed Central PMCID: PMC7056868.

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 Feb 25;117(8):3913-3914. doi: 10.1073/pnas.1922199117. Epub 2020 Feb 19. PubMed PMID: 32075921; PubMed Central PMCID: PMC7049110.

Aziz DB, Go ML, Dick T. Rifabutin Suppresses Inducible Clarithromycin Resistance in Mycobacterium abscessus by Blocking Induction of whiB7 and erm41. Antibiotics (Basel). 2020 Feb 10;9(2). doi: 10.3390/antibiotics9020072. PubMed PMID: 32050554; PubMed Central PMCID: PMC7168051.

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 Feb 5;522(2):374-380. doi: 10.1016/j.bbrc.2019.11.098. Epub 2019 Nov 21. PubMed PMID: 31761325.

Dick T, Shin SJ, Koh WJ, Dartois V, Gengenbacher M. Rifabutin Is Active against Mycobacterium abscessus in Mice. Antimicrob Agents Chemother. 2020 Jan 27;64(2). doi: 10.1128/AAC.01943-19. Print 2020 Jan 27. PubMed PMID: 31767722; PubMed Central PMCID: PMC6985736.

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 Jan 27;64(2). doi: 10.1128/AAC.01540-19. Print 2020 Jan 27. PubMed PMID: 31712198; PubMed Central PMCID: PMC6985740.