IN SILICO IDENTIFICATION OF NATURAL PRODUCTS WITH ANTITUBERCULOSIS ACTIVITY FOR THE INHIBITION OF INHA AND ETHR PROTEINS FROM MYCOBACTERIUM TUBERCULOSIS

Authors

  • DANNI RAMDHANI 1Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia https://orcid.org/0000-0001-9854-5735
  • SRI AGUNG FITRI KUSUMA Department of Biology Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang-45363, West Java, Indonesia https://orcid.org/0000-0001-8342-0112

DOI:

https://doi.org/10.22159/ijap.2023.v15s2.31

Keywords:

Tuberculosis, Mycobacterium tuberculosis,, Multidrug resistance, Antibiotic, Natural products, Reverse docking

Abstract

Objective: The rise of Mycobacterium tuberculosis (MT) strains that are resistant to antibiotics poses a serious threat to public health, particularly in middle and low-income countries. The important role of natural products (NPs) in the discovery of new drugs to treat infectious diseases is driving the success of synthetic chemistry in the production of new drugs. In our study, 15 NPs were selected to be investigated for their anti-TB properties by in silico method.

Methods: Molecular reverse docking approach to predict the interaction of NPs as a drug lead against the regulatory proteins (InhA, EthR) of MT. For each mycobacterial target, the docking scores/binding free energies were predicted and calculated using AutoDock Vina along with the physicochemical and structural characteristics of the NPs, and they were compared to the established inhibitor (control) drugs.

Results: The specific interactions of luteolin, piperine, butein, tiliacorinine against the targets InhA and EthA (-9.1 and-6.7 kcal. mol-1;-9.1 and-8.4 kcal. mol-1;-8.4 and-6.6 kcal. mol-1;-8.3 and-7.6 kcal. mol-1) had significantly superior docking scores compared to controls.

Conclusion: Our research proposed these compounds as potent therapeutic agents for the development of anti-tuberculosis medications; however, additional in vitro and in vivo testing is required to confirm their potential as novel therapeutics and mechanisms of action.

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References

Gordon SV, Parish T. Microbe profile: mycobacterium tuberculosis: humanity’s deadly microbial foe. Microbiology (Reading). 2018;164(4):437-9. doi: 10.1099/mic.0.000601, PMID 29465344.

Rapid communication on forthcoming changes to the programmatic management of tuberculosis preventive treatment. Available from: https://www.who.int/tb/publications/2020/WHORapidCommunication_TPT2020.pdf?ua=1. [Last accessed on 10 Aug 2023]

Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb Perspect Med. 2015;5(9):a017863. doi: 10.1101/cshperspect.a017863, PMID 25918181.

Dookie N, Rambaran S, Padayatchi N, Mahomed S, Naidoo K. Evolution of drug resistance in mycobacterium tuberculosis: a review on the molecular determinants of resistance and implications for personalized care. J Antimicrob Chemother. 2018;73(5):1138-51. doi: 10.1093/jac/dkx506, PMID 29360989.

Velayati AA, Farnia P, Farahbod AM. Overview of drug-resistant tuberculosis worldwide. Int J Mycobacteriol. 2016;5Suppl 1:S161. doi: 10.1016/j.ijmyco.2016.09.066, PMID 28043527.

Suarez I, Funger SM, Kroger S, Rademacher J, Fatkenheuer G, Rybniker J. The diagnosis and treatment of tuberculosis. Dtsch Arztebl Int. 2019;116(43):729-35. doi: 10.3238/arztebl.2019.0729, PMID 31755407.

Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, Prasad T. Recent updates on drug resistance in Mycobacterium tuberculosis. J Appl Microbiol. 2020;128(6):1547-67. doi: 10.1111/jam.14478, PMID 31595643.

Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C. Bedaquiline in the treatment of multidrug and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47(2):564-74. doi: 10.1183/13993003.00724-2015, PMID 26647431.

Li Y, Sun F, Zhang W. Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: promising but challenging. Drug Dev Res. 2019;80(1):98-105. doi: 10.1002/ddr.21498, PMID 30548290.

Liu Y, Matsumoto M, Ishida H, Ohguro K, Yoshitake M, Gupta R. Delamanid: from discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis (Edinb). 2018;111:20-30. doi: 10.1016/j.tube.2018.04.008, PMID 30029909.

Zaman K. Tuberculosis: a global health problem. J Health Popul Nutr. 2010;28(2):111-3. doi: 10.3329/jhpn.v28i2.4879, PMID 20411672.

Loddenkempe R, Lipman M, Zumla A. Clinical aspects of adult tuberculosis. Cold Spring Harb Perspect Med. 2016;6(1):a017848.

Munoz L, Stagg HR, Abubakar I. Diagnosis and management of latent tuberculosis infection. Cold Spring Harb Perspect Med. 2015;5(11):a017830. doi: 10.1101/cshperspect.a017830, PMID 26054858.

Daffe M, Laneelle MA, Asselineau C, Levy Frebault V, David H. Taxonomic value of mycobacterial fatty acids: proposal for a method of analysis. Ann Microbiol (Paris). 1983;134B(2):241-56, PMID 6651121.

Dubnau E, Chan J, Raynaud C, Mohan VP, Laneelle MA, Yu K. Oxygenated mycolic acids are necessary for virulence of Mycobacterium tuberculosis in mice. Mol Microbiol. 2000;36(3):630-7. doi: 10.1046/j.1365-2958.2000.01882.x, PMID 10844652.

Dkhar HK, Nanduri R, Mahajan S, Dave S, Saini A, Somavarapu AK. Mycobacterium tuberculosis keto-mycolic acid and macrophage nuclear receptor TR4 modulate foamy biogenesis in granulomas: a case of a heterologous and noncanonical ligand-receptor pair. J Immunol. 2014;193(1):295-305. doi: 10.4049/jimmunol.1400092, PMID 24907344.

Dessen A, Quemard A, Blanchard JS, Jacobs WR, Sacchettini JC. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science. 1995;267(5204):1638-41. doi: 10.1126/science.7886450, PMID 7886450.

Engohang Ndong J, Baillat D, Aumercier M, Bellefontaine F, Besra GS, Locht C. EthR, a repressor of the TetR/CamR family implicated in ethionamide resistance in mycobacteria, octamerizes cooperatively on its operator. Mol Microbiol. 2004;51(1):175-88. doi: 10.1046/j.1365-2958.2003.03809.x, PMID 14651620.

Hameed HMA, Islam MM, Chhotaray C, Wang C, Liu Y, Tan Y. Molecular targets related drug resistance mechanisms in MDR, XDR, and TDR-Mycobacterium tuberculosis strains. Front Cell Infect Microbiol. 2018;8:114. doi: 10.3389/fcimb.2018.00114, PMID 29755957.

Takayama K, Wang L, David HL. Effect of isoniazid on the in vivo mycolic acid synthesis, cell growth, and viability of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1972;2(1):29-35. doi: 10.1128/AAC.2.1.29, PMID 4208567.

Baptista R, Bhowmick S, Shen J, Mur LAJ. Molecular docking suggests the targets of anti-mycobacterial natural products. Molecules. 2021;26(2):475. doi: 10.3390/molecules26020475, PMID 33477495.

Willand N, Dirie B, Carette X, Bifani P, Singhal A, Desroses M. Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nat Med. 2009;15(5):537-44. doi: 10.1038/nm.1950, PMID 19412174.

Hoffmann C, Leis A, Niederweis M, Plitzko JM, Engelhardt H. Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci USA. 2008;105(10):3963-7. doi: 10.1073/pnas.0709530105, PMID 18316738.

Alderwick LJ, Birch HL, Mishra AK, Eggeling L, Besra GS. Structure, function and biosynthesis of the Mycobacterium tuberculosis cell wall: arabinogalactan and lipoarabinomannan assembly with a view to discovering new drug targets. Biochem Soc Trans. 2007;35(5):1325-8. doi: 10.1042/BST0351325, PMID 17956343.

Lienhardt C, Raviglione M, Spigelman M, Hafner R, Jaramillo E, Hoelscher M. New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future. J Infect Dis. 2012;205Suppl 2:S241-9. doi: 10.1093/infdis/jis034, PMID 22448022.

Velayati AA, Farnia P, Farahbod AM. Overview of drug-resistant tuberculosis worldwide. Int J Mycobacteriol. 2016;5Suppl 1:S161. doi: 10.1016/j.ijmyco.2016.09.066, PMID 28043527.

World Health Organization. END TB global tuberculosis report 2017. Geneva, Switzerland: World Health Organization; 2017.

Duan X, Xiang X, Xie J. Crucial components of mycobacterium type II fatty acid biosynthesis (Fas-II) and their inhibitors. FEMS Microbiol Lett. 2014;360(2):87-99. doi: 10.1111/1574-6968.12597, PMID 25227413.

DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proc Natl Acad Sci USA. 2000;97(17):9677-82. doi: 10.1073/pnas.97.17.9677, PMID 10944230.

Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-91. doi: 10.1002/jcc.21256, PMID 19399780.

Venugopala KN, Chandrashekharappa S, Deb PK, Tratrat C, Pillay M, Chopra D. Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme. J Enzyme Inhib Med Chem. 2021;36(1):1471-86. doi: 10.1080/14756366.2021.1919889.

Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiol Rev. 2017;41(3):354-73. doi: 10.1093/femsre/fux011, PMID 28369307.

Sarkar B, Islam SS, Ullah MA, Hossain S, Prottoy MNI, Araf Y. Computational assessment and pharmacological property breakdown of eight patented and candidate drugs against four intended targets in Alzheimer’s disease. Adv Biosci Biotechnol. 2019;10(11):405-30. doi: 10.4236/abb.2019.1011030.

Ullah MA, Johora FT, Sarkar B, Araf Y, Rahman MH. Curcumin analogs as the inhibitors of TLR4 pathway in inflammation and their drug like potentialities: a computer based study. J Recept Signal Transduct Res. 2020;40(4):324-38. doi: 10.1080/10799893.2020.1742741, PMID 32223496.

Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235-49. doi: 10.1016/s1056-8719(00)00107-6, PMID 11274893.

Published

18-12-2023

How to Cite

RAMDHANI, D., & KUSUMA, S. A. F. (2023). IN SILICO IDENTIFICATION OF NATURAL PRODUCTS WITH ANTITUBERCULOSIS ACTIVITY FOR THE INHIBITION OF INHA AND ETHR PROTEINS FROM MYCOBACTERIUM TUBERCULOSIS. International Journal of Applied Pharmaceutics, 15(2), 169–174. https://doi.org/10.22159/ijap.2023.v15s2.31

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