New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis


Autoři: Andréanne Lupien aff001;  Caroline Shi-Yan Foo aff001;  Svetlana Savina aff002;  Anthony Vocat aff001;  Jérémie Piton aff001;  Natalia Monakhova aff002;  Andrej Benjak aff001;  Dirk A. Lamprecht aff003;  Adrie J. C. Steyn aff003;  Kevin Pethe aff005;  Vadim A. Makarov aff002;  Stewart T. Cole aff001
Působiště autorů: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland aff001;  Department of Stresses of Microorganisms, A. N. Bach Institute of Biochemistry, Moscow, Russian Federation aff002;  Africa Health Research Institute, Durban, South Africa aff003;  Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America aff004;  Lee Kong Chian School of Medicine and School of Biological Sciences, Nanyang Technological University, Singapore aff005;  Institut Pasteur, rue du Docteur Roux, France aff006
Vyšlo v časopise: New 2-Ethylthio-4-methylaminoquinazoline derivatives inhibiting two subunits of cytochrome bc1 in Mycobacterium tuberculosis. PLoS Pathog 16(1): e32767. doi:10.1371/journal.ppat.1008270
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008270

Souhrn

The emergence of multi-drug (MDR-TB) and extensively-drug resistant tuberculosis (XDR-TB) is a major threat to the global management of tuberculosis (TB) worldwide. New chemical entities are of need to treat drug-resistant TB. In this study, the mode of action of new, potent quinazoline derivatives was investigated against Mycobacterium tuberculosis (M. tb). Four derivatives 11626141, 11626142, 11626252 and 11726148 showed good activity (MIC ranging from 0.02–0.09 μg/mL) and low toxicity (TD50 ≥ 5μg/mL) in vitro against M. tb strain H37Rv and HepG2 cells, respectively. 11626252 was the most selective compound from this series. Quinazoline derivatives were found to target cytochrome bc1 by whole-genome sequencing of mutants selected with 11626142. Two resistant mutants harboured the transversion T943G (Trp312Gly) and the transition G523A (Gly175Ser) in the cytochrome bc1 complex cytochrome b subunit (QcrB). Interestingly, a third mutant QuinR-M1 contained a mutation in the Rieske iron-sulphur protein (QcrA) leading to resistance to quinazoline and other QcrB inhibitors, the first report of cross-resistance involving QcrA. Modelling of both QcrA and QcrB revealed that all three resistance mutations are located in the stigmatellin pocket, as previously observed for other QcrB inhibitors such as Q203, AX-35, and lansoprazole sulfide (LPZs). Further analysis of the mode of action in vitro revealed that 11626252 exposure leads to ATP depletion, a decrease in the oxygen consumption rate and also overexpression of the cytochrome bd oxidase in M. tb. Our findings suggest that quinazoline-derived compounds are a new and attractive chemical entity for M. tb drug development targeting two separate subunits of the cytochrome bc1 complex.

Klíčová slova:

Drug metabolism – Drug therapy – Extensively drug-resistant tuberculosis – Multi-drug-resistant tuberculosis – Mycobacterium tuberculosis – Respiratory infections – Transcriptome analysis – Tuberculosis


Zdroje

1. WHO | Global tuberculosis report 2017. In: WHO [Internet]. [cited 22 Feb 2018]. Available: http://www.who.int/tb/publications/global_report/en/

2. Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi O. Modern advances in heterocyclic chemistry in drug discovery. Org Biomol Chem. 2016;14: 6611–6637. doi: 10.1039/c6ob00936k 27282396

3. Parker MA, Kurrasch DM, Nichols DE. The Role of Lipophilicity in Determining Binding Affinity and Functional Activity for 5-HT2A Receptor Ligands. Bioorg Med Chem. 2008;16: 4661–4669. doi: 10.1016/j.bmc.2008.02.033 18296055

4. Jafari E, Khajouei MR, Hassanzadeh F, Hakimelahi GH, Khodarahmi GA. Quinazolinone and quinazoline derivatives: recent structures with potent antimicrobial and cytotoxic activities. Res Pharm Sci. 2016;11: 1–14. 27051427

5. Selvam TP, Sivakumar A, Prabhu PP. Design and synthesis of quinazoline carboxylates against Gram-positive, Gram-negative, fungal pathogenic strains, and Mycobacterium tuberculosis. J Pharm Bioallied Sci. 2014;6: 278–284. doi: 10.4103/0975-7406.142960 25400411

6. Odingo J, O’Malley T, Kesicki EA, Alling T, Bailey MA, Early J, et al. Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents. Bioorg Med Chem. 2014;22: 6965–6979. doi: 10.1016/j.bmc.2014.10.007 25456390

7. Zhang M, Sala C, Hartkoorn RC, Dhar N, Mendoza-Losana A, Cole ST. Streptomycin-Starved Mycobacterium tuberculosis 18b, a Drug Discovery Tool for Latent Tuberculosis. Antimicrob Agents Chemother. 2012;56: 5782–5789. doi: 10.1128/AAC.01125-12 22926567

8. Wiseman B, Nitharwal RG, Fedotovskaya O, Schäfer J, Guo H, Kuang Q, et al. Structure of a functional obligate complex III2IV2 respiratory supercomplex from Mycobacterium smegmatis. Nat Struct Mol Biol. 2018;25: 1128–1136. doi: 10.1038/s41594-018-0160-3 30518849

9. Arora K, Ochoa-Montaño B, Tsang PS, Blundell TL, Dawes SS, Mizrahi V, et al. Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58: 6962–6965. doi: 10.1128/AAC.03486-14 25155596

10. Esser L, Quinn B, Li Y-F, Zhang M, Elberry M, Yu L, et al. Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc(1) complex. J Mol Biol. 2004;341: 281–302. doi: 10.1016/j.jmb.2004.05.065 15312779

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

12. Lamprecht DA, Finin PM, Rahman MA, Cumming BM, Russell SL, Jonnala SR, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun. 2016;7: 12393. doi: 10.1038/ncomms12393 27506290

13. Moosa A, Lamprecht DA, Arora K, Barry CE, Boshoff HIM, Ioerger TR, et al. Susceptibility of Mycobacterium tuberculosis Cytochrome bd Oxidase Mutants to Compounds Targeting the Terminal Respiratory Oxidase, Cytochrome c. Antimicrob Agents Chemother. 2017;61: e01338–17. doi: 10.1128/AAC.01338-17 28760899

14. Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, et al. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015;6. doi: 10.1038/ncomms8659 26158909

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

16. O’Malley T, Alling T, Early JV, Wescott HA, Kumar A, Moraski GC, et al. Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels. Antimicrob Agents Chemother. 2018;62: e02439–17. doi: 10.1128/AAC.02439-17 29632008

17. Li C, Li Q, Zhang Y, Gong Z, Ren S, Li P, et al. Characterization and function of Mycobacterium tuberculosis H37Rv Lipase Rv1076 (LipU). Microbiol Res. 2017;196: 7–16. doi: 10.1016/j.micres.2016.12.005 28164792

18. Muñoz‐Elías EJ, Upton AM, Cherian J, McKinney JD. Role of the methylcitrate cycle in Mycobacterium tuberculosis metabolism, intracellular growth, and virulence. Mol Microbiol. 2006;60: 1109–1122. doi: 10.1111/j.1365-2958.2006.05155.x 16689789

19. Kalia NP, Hasenoehrl EJ, Ab Rahman NB, Koh VH, Ang MLT, Sajorda DR, et al. Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci U S A. 2017;114: 7426–7431. doi: 10.1073/pnas.1706139114 28652330

20. Lakshminarayana SB, Huat TB, Ho PC, Manjunatha UH, Dartois V, Dick T, et al. Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents. J Antimicrob Chemother. 2015;70: 857–867. doi: 10.1093/jac/dku457 25587994

21. Shi L, Sohaskey CD, Kana BD, Dawes S, North RJ, Mizrahi V, et al. Changes in energy metabolism of Mycobacterium tuberculosis in mouse lung and under in vitro conditions affecting aerobic respiration. Proc Natl Acad Sci. 2005;102: 15629–15634. doi: 10.1073/pnas.0507850102 16227431

22. Lu X, Williams Z, Hards K, Tang J, Cheung C-Y, Aung HL, et al. Pyrazolo[1,5- a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis. ACS Infect Dis. 2019;5: 239–249. doi: 10.1021/acsinfecdis.8b00225 30485737

23. Small JL, Park SW, Kana BD, Ioerger TR, Sacchettini JC, Ehrt S. Perturbation of Cytochrome c Maturation Reveals Adaptability of the Respiratory Chain in Mycobacterium tuberculosis. mBio. 2013;4: e00475–13. doi: 10.1128/mBio.00475-13 24045640

24. Berry EA, Guergova-Kuras M, Huang LS, Crofts AR. Structure and function of cytochrome bc complexes. Annu Rev Biochem. 2000;69: 1005–1075. doi: 10.1146/annurev.biochem.69.1.1005 10966481

25. Gong H, Li J, Xu A, Tang Y, Ji W, Gao R, et al. An electron transfer path connects subunits of a mycobacterial respiratory supercomplex. Science. 2018;362. doi: 10.1126/science.aat8923 30361386

26. Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis | PNAS. [cited 13 Nov 2019]. Available: https://www.pnas.org/content/110/16/6554.short

27. Palomino J-C, Martin A, Camacho M, Guerra H, Swings J, Portaels F. Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2002;46: 2720–2722. doi: 10.1128/AAC.46.8.2720-2722.2002 12121966

28. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

29. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012;9: 357–359. doi: 10.1038/nmeth.1923 22388286

30. Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. ArXiv12073907 Q-Bio. 2012. Available: http://arxiv.org/abs/1207.3907

31. Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22: 568–576. doi: 10.1101/gr.129684.111 22300766

32. The PyMOL Molecular Graphics System. Schrödinger, LLC;

33. Balasubramanian V, Pavelka MS, Bardarov SS, Martin J, Weisbrod TR, McAdam RA, et al. Allelic exchange in Mycobacterium tuberculosis with long linear recombination substrates. J Bacteriol. 1996;178: 273–279. doi: 10.1128/jb.178.1.273-279.1996 8550428

34. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30: 923–930. doi: 10.1093/bioinformatics/btt656 24227677

35. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15: 550. doi: 10.1186/s13059-014-0550-8 25516281


Článek vyšel v časopise

PLOS Pathogens


2020 Číslo 1

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Nová éra v léčbě migrény
nový kurz
Autoři: MUDr. Eva Medová, MUDr. Tomáš Nežádal, Ph.D.

Význam nutraceutik u kardiovaskulárních onemocnění
Autoři:

Pneumowebinář
Autoři:

White paper - jak vidíme optimální péči o zubní náhrady
Autoři: MUDr. Jindřich Charvát, CSc.

Faktory ovlivňující léčbu levotyroxinem

Všechny kurzy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se