The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study
Abstract
1. Introduction
2. Materials and Methods
2.1. Molecular Docking
2.2. Cell Culture
2.3. Microplate Alamar Blue Assay (MABA)
2.4. Evaluation of Growth Inhibition of Mtb
2.5. Cytotoxicity Assay
2.6. CFUs/mL Assay
2.7. Statistical Analysis
3. Results
3.1. Molecule Selection
3.2. Paroxetine and Nebivolol Show Anti-Mycobacterial Tuberculosis Activity
3.3. Paroxetine and Nebivolol Reduce CFU/mL Counts in Macrophages
4. Discussion
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- World Health Organization. Global Tuberculosis Report 2023; World Health Organization: Geneva, Switzerland, 2023. [Google Scholar]
- World Health Organization. The End TB Strategy. Available online: https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategy (accessed on 4 June 2024).
- Liu, Y.; Tong, Z.; Shi, J.; Li, R.; Upton, M.; Wang, Z. Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria. Theranostics 2021, 11, 4910–4928. [Google Scholar] [CrossRef]
- Sharma, K.; Ahmed, F.; Sharma, T.; Grover, A.; Agarwal, M.; Grover, S. Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade. ACS Omega 2023, 8, 17362–17380. [Google Scholar] [CrossRef]
- Conradie, F.; Bagdasaryan, T.R.; Borisov, S.; Howell, P.; Mikiashvili, L.; Ngubane, N.; Samoilova, A.; Skornykova, S.; Tudor, E.; Variava, E.; et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N. Engl. J. Med. 2022, 387, 810–823. [Google Scholar] [CrossRef]
- Stadler, J.A.M.; Maartens, G.; Meintjes, G.; Wasserman, S. Clofazimine for the treatment of tuberculosis. Front. Pharmacol. 2023, 14, 1100488. [Google Scholar] [CrossRef]
- Margolin, W. FtsZ and the division of prokaryotic cells and organelles. Nat. Rev. Mol. Cell Biol. 2005, 6, 862–871. [Google Scholar] [CrossRef]
- Nazir, A.; Harinarayanan, R. Inactivation of Cell Division Protein FtsZ by SulA Makes Lon Indispensable for the Viability of a ppGpp0 Strain of Escherichia coli. J. Bacteriol. 2015, 198, 688–700. [Google Scholar] [CrossRef] [PubMed]
- White, E.L.; Suling, W.J.; Ross, L.J.; Seitz, L.E.; Reynolds, R.C. 2-Alkoxycarbonylaminopyridines: Inhibitors of Mycobacterium tuberculosis FtsZ. J. Antimicrob. Chemother. 2002, 50, 111–114. [Google Scholar] [CrossRef] [PubMed]
- Jaiswal, R.; Beuria, T.K.; Mohan, R.; Mahajan, S.K.; Panda, D. Totarol inhibits bacterial cytokinesis by perturbing the assembly dynamics of FtsZ. Biochemistry 2007, 46, 4211–4220. [Google Scholar] [CrossRef]
- Yamamoto, S.; Saito, R.; Nakamura, S.; Sogawa, H.; Karpov, P.; Shulga, S.; Blume, Y.; Kurita, N. Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations. Antibiotics 2020, 9, 846. [Google Scholar] [CrossRef] [PubMed]
- Akinpelu, O.I.; Kumalo, H.M.; Mhlongo, S.I.; Mhlongo, N.N. Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb-FtsZ polymerisation through ligand-based virtual screening and molecular dynamics simulations. J. Mol. Recognit. 2022, 35, e2940. [Google Scholar] [CrossRef]
- Lin, Y.; Zhang, H.; Zhu, N.; Wang, X.; Han, Y.; Chen, M.; Jiang, J.; Si, S. Identification of TB-E12 as a novel FtsZ inhibitor with anti-tuberculosis activity. Tuberculosis 2018, 110, 79–85. [Google Scholar] [CrossRef] [PubMed]
- Margalit, D.N.; Romberg, L.; Mets, R.B.; Hebert, A.M.; Mitchison, T.J.; Kirschner, M.W.; RayChaudhuri, D. Targeting cell division: Small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality. Proc. Natl. Acad. Sci. USA 2004, 101, 11821–11826. [Google Scholar] [CrossRef]
- Alnami, A.; Norton, R.S.; Pena, H.P.; Haider, S.; Kozielski, F. Conformational Flexibility of A Highly Conserved Helix Controls Cryptic Pocket Formation in FtsZ. J. Mol. Biol. 2021, 433, 167061. [Google Scholar] [CrossRef] [PubMed]
- Irwin, J.J.; Tang, K.G.; Young, J.; Dandarchuluun, C.; Wong, B.R.; Khurelbaatar, M.; Moroz, Y.S.; Mayfield, J.; Sayle, R.A. ZINC20—A Free Ultralarge-Scale Chemical Database for Ligand Discovery. J. Chem. Inf. Model. 2020, 60, 6065–6073. [Google Scholar] [CrossRef] [PubMed]
- Rodríguez-Carlos, A.; Jacobo-Delgado, Y.; Santos-Mena, A.O.; García-Hernández, M.H.; De Jesus-Gonzalez, L.A.; Lara-Ramirez, E.E.; Rivas-Santiago, B. Histone deacetylase (HDAC) inhibitors- based drugs are effective to control Mycobacterium tuberculosis infection and promote the sensibility for rifampicin in MDR strain. Mem. Inst. Oswaldo Cruz 2023, 118, e230143. [Google Scholar] [CrossRef] [PubMed]
- Henao Arias, D.C.; Toro, L.J.; Téllez Ramirez, G.A.; Osorio-Méndez, J.F.; Rodríguez-Carlos, A.; Valle, J.; Marín-Luevano, S.P.; Rivas-Santiago, B.; Andreu, D.; Castaño Osorio, J.C. Novel antimicrobial cecropins derived from O. curvicornis and D. satanas dung beetles. Peptides 2021, 145, 170626. [Google Scholar] [CrossRef] [PubMed]
- Rivas-Santiago, B.; de Haro-Acosta, J.; Carlos, A.R.; Garcia-Hernandez, M.H.; Serrano, C.J.; Gonzalez-Curiel, I.; Rivas-Santiago, C. Nicotine promotes Mycobacterium tuberculosis H37Rv growth and overexpression of virulence genes. Microbiol. Immunol. 2023, 67, 365–376. [Google Scholar] [CrossRef] [PubMed]
- Scott, L.J. Sitagliptin: A Review in Type 2 Diabetes. Drugs 2017, 77, 209–224. [Google Scholar] [CrossRef] [PubMed]
- Foletto, V.S.; da Rosa, T.F.; Serafin, M.B.; Bottega, A.; Franco, L.N.; de Paula, B.R.; Hörner, R. Repositioning of antidepressant drugs and synergistic effect with ciprofloxacin against multidrug-resistant bacteria. World J. Microbiol. Biotechnol. 2021, 37, 53. [Google Scholar] [CrossRef]
- Uma Priya, K.; Venkataramaiah, C.; Sreedhar, N.Y.; Raju, C.N. Design, synthesis, characterization and in vitro, in vivo and in silico antimicrobial and antiinflammatory activities of a new series of sulphonamide and carbamate derivatives of a nebivolol intermediate. RSC Adv. 2021, 11, 3897–3916. [Google Scholar] [CrossRef]
- Spencer, C.M.; Goa, K.L. Atovaquone. A review of its pharmacological properties and therapeutic efficacy in opportunistic infections. Drugs 1995, 50, 176–196. [Google Scholar] [CrossRef] [PubMed]
- Capela, R.; Félix, R.; Clariano, M.; Nunes, D.; Perry, M.D.; Lopes, F. Target Identification in Anti-Tuberculosis Drug Discovery. Int. J. Mol. Sci. 2023, 24, 10482. [Google Scholar] [CrossRef] [PubMed]
- Barrows, J.M.; Goley, E.D. FtsZ dynamics in bacterial division: What, how, and why? Curr. Opin. Cell Biol. 2021, 68, 163–172. [Google Scholar] [CrossRef] [PubMed]
- Mohanty, M.; Mohanty, P.S. Molecular docking in organic, inorganic, and hybrid systems: A tutorial review. Monatshefte Chem. 2023, 154, 683–707. [Google Scholar] [CrossRef] [PubMed]
- Trivedi, P.; Chaturvedi, V. Interactive effect of oral anti-hyperglycaemic or anti-hypertensive drugs on the inhibitory and bactericidal activity of first line anti-TB drugs against M. tuberculosis. PLoS ONE 2023, 18, e0292397. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez-Carlos, A.; Valdez-Miramontes, C.; Marin-Luevano, P.; González-Curiel, I.; Enciso-Moreno, J.A.; Rivas-Santiago, B. Metformin promotes Mycobacterium tuberculosis killing and increases the production of human β-defensins in lung epithelial cells and macrophages. Microbes Infect. 2020, 22, 111–118. [Google Scholar] [CrossRef]
- Erasmus, C.; Aucamp, J.; Smit, F.J.; Seldon, R.; Jordaan, A.; Warner, D.F.; N’Da, D.D. Synthesis and comparison of in vitro dual anti-infective activities of novel naphthoquinone hybrids and atovaquone. Bioorg. Chem. 2021, 114, 105118. [Google Scholar] [CrossRef] [PubMed]
- Pereira, T.C.; de Menezes, R.T.; de Oliveira, H.C.; de Oliveira, L.D.; Scorzoni, L. In vitro synergistic effects of fluoxetine and paroxetine in combination with amphotericin B against Cryptococcus neoformans. Pathog. Dis. 2021, 79, ftab001. [Google Scholar] [CrossRef] [PubMed]
- Cabral, V.P.; Rodrigues, D.S.; Barbosa, A.D.; Moreira, L.E.; Sá, L.G.; Silva, C.R.; Neto, J.B.; Silva, J.; Marinho, E.S.; Santos, H.S.; et al. Antibacterial activity of paroxetine against Staphylococcus aureus and possible mechanisms of action. Future Microbiol. 2023, 18, 415–426. [Google Scholar] [CrossRef]
- Caldara, M.; Marmiroli, N. Antimicrobial Properties of Antidepressants and Antipsychotics-Possibilities and Implications. Pharmaceuticals 2021, 14, 915. [Google Scholar] [CrossRef]
- Shen, R.; Zong, K.; Liu, J.; Zhang, L. Risk Factors for Depression in Tuberculosis Patients: A Meta-Analysis. Neuropsychiatr. Dis. Treat. 2022, 18, 847–866. [Google Scholar] [CrossRef] [PubMed]
- Trenton, A.J.; Currier, G.W. Treatment of Comorbid Tuberculosis and Depression. Prim. Care Companion J. Clin. Psychiatry 2001, 3, 236–243. [Google Scholar] [CrossRef] [PubMed]
- Caccia, S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin. Pharmacokinet. 1998, 34, 281–302. [Google Scholar] [CrossRef] [PubMed]
- Prisant, L.M. Nebivolol: Pharmacologic Profile of an Ultraselective, Vasodilatory β1-Blocker. J. Clin. Pharmacol. 2008, 48, 225–239. [Google Scholar] [CrossRef]
- Diego, L.M.; Jazmin, F.M.; Diana, R.H.; German-Isauro, G.F.; Salvador, F.C.; Maria-Elena, H.C. Modulation of TNF-α, interleukin-6, and interleukin-10 by nebivolol-valsartan and nebivolol-lisinopril polytherapy in SHR rats. Pharmacol. Res. Perspect. 2024, 12, e1189. [Google Scholar] [CrossRef]
ZINC ID | Vina Score (kCal/mol) | FDA- Approved Drug | Structure | Reported Activity | Amino Acid Residues | Citation |
---|---|---|---|---|---|---|
1489478 | −9.4 | Sitagliptin | Inhibition of dipeptidyl peptidase-4 (DPP-4) | GLU-136 ARG-140 | [20] | |
527386 | −9 | Paroxetine | Selective serotonin reuptake inhibitor (SSRI) | THR-106 GLY-105 GLY-19 GLU-102 | [21] | |
4213946 | −8.6 | Nebivolol | Beta-blocker | ASN-22 THR-106 GLY-19 ARG-140 GLU-136 | [22] | |
12504271 | −8.5 | Atovaquone | Antimicrobial, antifungal | ARG-140 | [23] | |
−8.5 | GDP guanosine diphosphate | ASP-184 GLU-136 ARG-140 GLY-19 GLY-18 ANS-22 THR-106 GLY-105 GLY-107 |
FDA-Approved Drug | H37Rv (µg/mL) | MDR (µg/mL) |
---|---|---|
Rifampicin | 0.5 | >1 |
Streptomycin | 0.5 | 0.5 |
Sitagliptin | >150 | >150 |
Atovaquone | >10 | >10 |
Paroxetine | 25 | 25 |
Nebivolol | 25 | 25 |
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Tovar-Nieto, A.M.; Flores-Padilla, L.E.; Rivas-Santiago, B.; Trujillo-Paez, J.V.; Lara-Ramirez, E.E.; Jacobo-Delgado, Y.M.; López-Ramos, J.E.; Rodríguez-Carlos, A. The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study. Microorganisms 2024, 12, 1505. https://doi.org/10.3390/microorganisms12081505
Tovar-Nieto AM, Flores-Padilla LE, Rivas-Santiago B, Trujillo-Paez JV, Lara-Ramirez EE, Jacobo-Delgado YM, López-Ramos JE, Rodríguez-Carlos A. The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study. Microorganisms. 2024; 12(8):1505. https://doi.org/10.3390/microorganisms12081505
Chicago/Turabian StyleTovar-Nieto, Andrea Michel, Luis Enrique Flores-Padilla, Bruno Rivas-Santiago, Juan Valentin Trujillo-Paez, Edgar Eduardo Lara-Ramirez, Yolanda M. Jacobo-Delgado, Juan Ernesto López-Ramos, and Adrián Rodríguez-Carlos. 2024. "The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study" Microorganisms 12, no. 8: 1505. https://doi.org/10.3390/microorganisms12081505
APA StyleTovar-Nieto, A. M., Flores-Padilla, L. E., Rivas-Santiago, B., Trujillo-Paez, J. V., Lara-Ramirez, E. E., Jacobo-Delgado, Y. M., López-Ramos, J. E., & Rodríguez-Carlos, A. (2024). The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study. Microorganisms, 12(8), 1505. https://doi.org/10.3390/microorganisms12081505