Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

English version

Autoři: Garrett C. Moraski ^aff001; Nathalie Deboosère ^aff002; Kate L. Marshall ^aff001; Heath A. Weaver ^aff001; Alexandre Vandeputte ^aff002; Courtney Hastings ^aff003; Lisa Woolhiser ^aff003; Anne J. Lenaerts ^aff003; Priscille Brodin ^aff002; Marvin J. Miller ^aff004
Působiště autorů: Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, United States of America ^aff001; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 –UMR 8204 –CIIL–Center for Infection and Immunity of Lille, Lille, France ^aff002; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, United States of America ^aff003; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America ^aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227224

Souhrn

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625–2.5 μM and mono-drug resistant potency ranging from 0.0017 to 7 μM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.

Klíčová slova:

Tuberculosis – Mycobacterium tuberculosis – Blood plasma – Spleen – Mouse models – High performance liquid chromatography – Macrophages – Animal models of infection

Zdroje

1. WHO (2018) Global Tuberculosis Report 2018. Geneva, Switzerland: WHO

2. Sotgiu G, Centis R, D'ambrosio L, Migliori GB (2015) Tuberculosis treatment and drug regimens. Cold Spring Harb Perspect Med 5: a017822. doi: 10.1101/cshperspect.a017822 25573773

3. Sahu S, Ditiu L, Zumla A (2019) After the UNGA High-Level Meeting on Tuberculosis—what next and how? The Lancet Global Health 7: e558–e560. doi: 10.1016/S2214-109X(19)30068-3 30876836

4. Mahajan R (2013) Bedaquiline: first FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res 3: 1–2. doi: 10.4103/2229-516X.112228 23776831

5. Pontali E, Raviglione MC, Migliori GB and the writing group members of the Global TB Network Clinical Trials Committee (2019) Regimens to treat multidrug-resistant tuberculosis: past, present and future perspectives. Eur Respir Rev 30: 190035.

6. Maxmen A (2019) Treatment for extreme drug-resistant tuberculosis wins US government approval. Nature doi: 10.1038/d41586-019-02464-0

7. Mahajan R (2013) Bedaquiline: first FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res 3: 1–2. doi: 10.4103/2229-516X.112228 23776831

8. Rao SP, Alonso S, Rand L, Dick T, Pethe K (2008) The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc Natl Acad Sci USA 105: 11945–11950. doi: 10.1073/pnas.0711697105 18697942

9. Moraski GC, Markley LD, Hipskind PA, Boshoff H, Cho S, et al. (2011) Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity. ACS Med Chem Lett 2: 466–470. doi: 10.1021/ml200036r 21691438

10. Moraski GC, Markley LD, Cramer J, Hipskind PA, Boshoff H, et al. (2013) Advancement of Imidazo[1,2-a]pyridines with Improved Pharmacokinetics and Nanomolar Activity Against Mycobacterium tuberculosis. ACS Med Chem Lett 4: 675–679. doi: 10.1021/ml400088y 23930153

11. Moraski GC, Oliver AG, Markley LD, Cho S, Franzblau SG, et al. (2014) Scaffold-switching: an exploration of 5,6-fused bicyclic heteroaromatics systems to afford antituberculosis activity akin to the imidazo[1,2-a]pyridine-3-carboxylates. Bioorg Med Chem Lett 24: 3493–3498. doi: 10.1016/j.bmcl.2014.05.062 24909079

12. Cheng Y, Moraski GC, Cramer J, Miller MJ, Schorey JS (2014) Bactericidal activity of an imidazo[1,2-a]pyridine using a mouse M. tuberculosis infection model. PLoS One 9: e87483. doi: 10.1371/journal.pone.0087483 24498115

13. Moraski GC, Miller PA, Bailey MA, Ollinger J, Parish T, et al. (2015) Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and "Anagrams" Generated Potent Antituberculosis Agents. ACS Infect Dis 1: 85–90. doi: 10.1021/id500008t 25984566

14. Moraski GC, Cheng Y, Cho S, Cramer JW, Godfrey A, et al. (2016) Imidazo[1,2-a]Pyridine-3-Carboxamides Are Active Antimicrobial Agents against Mycobacterium avium Infection In Vivo. Antimicrob Agents Chemother 60: 5018–5022. doi: 10.1128/AAC.00618-16 27216051

15. Ollinger J, Bailey MA, Moraski GC, Casey A, Florio S, et al. (2013) A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLoS One 8: e60531. doi: 10.1371/journal.pone.0060531 23593234

16. Pethe K, Bifani P, Jang J, Kang S, Park S, et al. (2013) Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19: 1157–1160. doi: 10.1038/nm.3262 23913123

17. Kang S, Kim RY, Seo MJ, Lee S, Kim YM, et al. (2014) Lead optimization of a novel series of imidazo[1,2-a]pyridine amides leading to a clinical candidate (Q203) as a multi- and extensively-drug-resistant anti-tuberculosis agent. J Med Chem 57: 5293–5305. doi: 10.1021/jm5003606 24870926

18. Abrahams KA, Cox JA, Spivey VL, Loman NJ, Pallen MJ, et al. (2012) Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS One 7: e52951. doi: 10.1371/journal.pone.0052951 23300833

19. O'Malley T, Alling T, Early JV, Wescott HA, Kumar A, et al. (2018) Imidazopyridine compounds inhibit mycobacterial growth by depleting ATP levels. Antimicrob Agents Chemother 62: e02439–17. doi: 10.1128/AAC.02439-17 29632008

20. Rybniker J, Vocat A, Sala C, Busso P, Pojer F, et al. (2015) Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nature Comm 6: 7659.

21. Foo CS, Lupien A, Kienle M, Vocat A, Benjak A, et al. (2018) Arylvinylpiperazine Amides, a New Class of Potent Inhibitors Targeting QcrB of Mycobacterium tuberculosis. Mbio. 9: e01276–18. doi: 10.1128/mBio.01276-18 30301850

22. Cleghorn LA, Ray PC, Odingo J, Kumar A, Wescott H, et al. (2018) Identification of morpholino thiophenes as novel Mycobacterium tuberculosis inhibitors, targeting QcrB. J Med Chem 61: 6592–6608. doi: 10.1021/acs.jmedchem.8b00172 29944372

23. Berube BJ, Parish T (2018) Combinations of respiratory chain inhibitors have enhanced bactericidal activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother 62: e01677–17. doi: 10.1128/AAC.01677-17 29061760

24. Chandrasekera NS, Berube BJ, Shetye G, Chettiar S, O’Malley T, et al. (2017) Improved phenoxyalkylbenzimidazoles with activity against Mycobacterium tuberculosis appear to target QcrB. ACS Infect Dis 3: 898–916. doi: 10.1021/acsinfecdis.7b00112 29035551

25. Arora K, Ochoa-Montaño B, Tsang PS, Blundell TL, Dawes SS, et al. (2014) Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58: 6962–6965. doi: 10.1128/AAC.03486-14 25155596

26. Moraski GC, Seeger N, Miller PA, Oliver AG, Boshoff HI, et al. (2016) Arrival of Imidazo[2,1-b]thiazole-5-carboxamides: Potent Anti-tuberculosis Agents That Target QcrB. ACS Infect Dis 2: 393–398. doi: 10.1021/acsinfecdis.5b00154 27627627

27. Moraski GC, Bristol R, Seeger N, Boshoff HI, Tsang PS, et al. (2017) Preparation and Evaluation of Potent Pentafluorosulfanyl‐Substituted Anti‐Tuberculosis Compounds. ChemMedChem 12: 1108–1115. doi: 10.1002/cmdc.201700170 28654200

28. Lu X, Tang J, Liu Z, Li M, Zhang T, et al. (2016) Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis. Bioorg Med Chem Lett 26: 5916–5919. doi: 10.1016/j.bmcl.2016.11.003 27839917

29. Tang J, Wang B, Wu T, Wan J, Tu Z, et al. (2015) Design, synthesis, and biological evaluation of pyrazolo[1,5-a]pyridine-3-carboxamides as novel antitubercular agents. ACS Med Chem Lett 6: 814–818. doi: 10.1021/acsmedchemlett.5b00176 26191372

30. Lu X, Williams Z, Hards K, Tang J, Cheung CY, et al. (2018) Pyrazolo[1,5-a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis. ACS Infect Dis 5: 239–249. doi: 10.1021/acsinfecdis.8b00225 30485737

31. Hu X, Wan B, Liu Y, Shen J, Franzblau SG, et al. (2019) Identification of Pyrazolo[1,5-a]pyridine-3-carboxamide Diaryl Derivatives as Drug Resistant Anti-tuberculosis Agents. ACS Med Chem Lett 10: 295–299 doi: 10.1021/acsmedchemlett.8b00410 30891129

32. Queval CJ, Song OR, Delorme V, Iantomasi R, Veyron-Churlet R, et al. (2014) A microscopic phenotypic assay for the quantification of intracellular mycobacteria adapted for high-throughput/high-content screening. J Vis Exp 83: e51114.

33. Song OR, Deboosere N, Delorme V, Queval CJ, Deloison G, et al. (2017) Phenotypic assays for Mycobacterium tuberculosis infection. Cytometry A 91: 983–994. doi: 10.1002/cyto.a.23129 28544095

34. Sprouffske K, Wagner A (2016) Growthcurver: an R package for obtaining interpretable metrics from microbial growth curves. BMC Bioinformatics 17: 172. doi: 10.1186/s12859-016-1016-7 27094401

35. Cho SH, Warit S, Wan B, Hwang CH, Pauli GF, et al. (2007) Low-Oxygen-Recovery Assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother 51: 1380–1385. doi: 10.1128/AAC.00055-06 17210775

36. Wayne LG, Hayes L (1998) Nitrate reduction as a marker for hypoxic shiftdown of Mycobacterium tuberculosis. Tuber Lung Dis. 79: 127–132. doi: 10.1054/tuld.1998.0015 10645451

37. Falzari K, Zhu Z, Pan D, Liu H, Hongmanee P, et al. (2005) In vitro and in vivo activities of macrolide derivatives against Mycobacterium tuberculosis. Antimicrob Agents Chemother 49: 1447–1454. doi: 10.1128/AAC.49.4.1447-1454.2005 15793125

38. Brodin P, Poquet Y, Levillain F, Peguillet I, Larrouy-Maumus G, et al. (2010) High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. PLoS Pathog 6: e1001100. doi: 10.1371/journal.ppat.1001100 20844580

39. Lenaerts AJ, Gruppo V, Marietta KS, Johnson CM, Driscoll DK, et al. (2005) Preclinical testing of the nitroimidazopyran PA-824 for activity against M. tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother 49: 2294–2301. doi: 10.1128/AAC.49.6.2294-2301.2005 15917524

40. Tiwari R, Moraski GC, Krchňák V, Miller PA, Colon-Martinez M, et al. (2013) Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents. J Am Chem Soc 135: 3539–3549. doi: 10.1021/ja311058q 23402278

41. Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1: 337–341. doi: 10.1016/j.ddtec.2004.11.007 24981612

42. Foti RS, Rock DA, Wienkers LC, Wahlstrom JL (2010) Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos 38: 981–987. doi: 10.1124/dmd.110.032094 20203109

43. Cook GM, Hards K, Dunn E, Heikal A, Nakatani Y, et al. (2017) Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Direction. Microbiol Spectr 5: doi: 10.1128/microbiolspec TBTB2-0014-2016.

44. Kalia NP, Hasenoehrl EJ, Ab Rahman NB, Koh VH, Ang ML, et al. (2017) Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci USA 114: 7426–7431. doi: 10.1073/pnas.1706139114 28652330

45. Lu P, Asseri AH, Kremer M, Maaskant J, Ummels R, et al. (2018) The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd. Sci Rep 8: 2625. doi: 10.1038/s41598-018-20989-8 29422632

46. Scherr N, Bieri R, Thomas SS, Chauffour A, Kalia NP, et al. (2018) Targeting the Mycobacterium ulcerans cytochrome bc1:aa3 for the treatment of Buruli ulcer. Nature Comm 9: 5370.

47. Liu Y, Gao Y, Liu J, Tan Y, Liu Z, et al. (2019) The compound TB47 is highly bactericidal against Mycobacterium ulcerans in a Buruli ulcer mouse model. Nature Comm 10: 524.

48. Converse PJ, Almeida DV, Tyagi S, Xu J, Nuermberger EL (2019) Shortening Buruli ulcer treatment with combination therapy targeting the respiratory chain and exploiting M. ulcerans gene decay. Antimicrob Agents Chemother 63: e00426–1. doi: 10.1128/AAC.00426-19 31036687

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

Souhrn

Klíčová slova:

Zdroje

PLOS One

Aktuální možnosti diagnostiky a léčby litiáz