From Proteome to Potential Drugs: Integration of Subtractive Proteomics and Ensemble Docking for Drug Repurposing against Pseudomonas aeruginosa RND Superfamily Proteins

  1. Urra, Gabriela 1
  2. Valdés-Muñoz, Elizabeth 4
  3. Suardiaz, Reynier 7
  4. Hernández-Rodríguez, Erix W. 12
  5. Palma, Jonathan M. 5
  6. Ríos-Rozas, Sofía E. 1
  7. Flores-Morales, Camila A. 8
  8. Alegría-Arcos, Melissa 6
  9. Yáñez, Osvaldo 6
  10. Morales-Quintana, Luis 9
  11. D’Afonseca, Vívian 3
  12. Bustos, Daniel 1
  1. 1 Laboratorio de Bioinformática y Química Computacional, Departamento de Medicina Traslacional, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile
  2. 2 Unidad de Bioinformática Clínica, Centro Oncológico, Facultad de Medicina, Universidad Católica del Maule, Talca 3480094, Chile
  3. 3 Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad Católica del Maule, Ave. San Miguel 3605, Talca 3466706, Chile
  4. 4 Doctorado en Biotecnología Traslacional, Facultad de Ciencias Agrarias y Forestales, Universidad Católica del Maule, Talca 3480094, Chile
  5. 5 Facultad de Ingeniería, Universidad de Talca, Curicó 3344158, Chile
  6. 6 Núcleo de Investigación en Data Science, Facultad de Ingeniería y Negocios, Universidad de las Américas, Santiago 7500000, Chile
  7. 7 Departamento de Química Física, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
  8. 8 Magíster en Ciencias de la Computación, Universidad Católica del Maule, Talca 3460000, Chile
  9. 9 Multidisciplinary Agroindustry Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Cinco Pte. N° 1670, Talca 3467987, Chile
Mostra les afiliacions +
Revista:
International Journal of Molecular Sciences

ISSN: 1422-0067

Any de publicació: 2024

Volum: 25

Número: 15

Pàgines: 8027

Tipus: Article

DOI: 10.3390/IJMS25158027 GOOGLE SCHOLAR lock_openAccés obert editor

Altres publicacions en: International Journal of Molecular Sciences

Resum

Pseudomonas aeruginosa (P. aeruginosa) poses a significant threat as a nosocomial pathogen due to its robust resistance mechanisms and virulence factors. This study integrates subtractive proteomics and ensemble docking to identify and characterize essential proteins in P. aeruginosa, aiming to discover therapeutic targets and repurpose commercial existing drugs. Using subtractive proteomics, we refined the dataset to discard redundant proteins and minimize potential cross-interactions with human proteins and the microbiome proteins. We identified 12 key proteins, including a histidine kinase and members of the RND efflux pump family, known for their roles in antibiotic resistance, virulence, and antigenicity. Predictive modeling of the three-dimensional structures of these RND proteins and subsequent molecular ensemble-docking simulations led to the identification of MK-3207, R-428, and Suramin as promising inhibitor candidates. These compounds demonstrated high binding affinities and effective inhibition across multiple metrics. Further refinement using non-covalent interaction index methods provided deeper insights into the electronic effects in protein–ligand interactions, with Suramin exhibiting superior binding energies, suggesting its broad-spectrum inhibitory potential. Our findings confirm the critical role of RND efflux pumps in antibiotic resistance and suggest that MK-3207, R-428, and Suramin could be effectively repurposed to target these proteins. This approach highlights the potential of drug repurposing as a viable strategy to combat P. aeruginosa infections.

Referències bibliogràfiques

  • Provenzani, (2020), Int. J. Clin. Pharm., 42, pp. 1016, 10.1007/s11096-020-01089-y
  • Thorpe, (2018), Health Aff., 37, pp. 662, 10.1377/hlthaff.2017.1153
  • World Health Organization (2024). WHO Bacterial Priority Pathogens List, 2024, World Health Organization.
  • Cendra, M.d.M., and Torrents, E. (2021). Pseudomonas aeruginosa biofilms and their partners in crime. Biotechnol. Adv., 49.
  • Rossi, (2021), Nat. Rev. Microbiol., 19, pp. 331, 10.1038/s41579-020-00477-5
  • Bustos, (2022), J. Chem. Inf. Model., 62, pp. 3067, 10.1021/acs.jcim.2c00059
  • Vincent, (2020), JAMA J. Am. Med. Assoc., 323, pp. 1478, 10.1001/jama.2020.2717
  • Vidaillac, (2021), Expert Rev. Respir. Med., 15, pp. 649, 10.1080/17476348.2021.1906225
  • Adamo, (2004), Am. J. Respir. Cell Mol. Biol., 30, pp. 627, 10.1165/rcmb.2003-0260OC
  • Soong, (2004), J. Clin. Investig., 113, pp. 1482, 10.1172/JCI200420773
  • Ozer, (2021), Sci. Adv., 7, pp. eabg8581, 10.1126/sciadv.abg8581
  • Colclough, (2020), Future Microbiol., 15, pp. 143, 10.2217/fmb-2019-0235
  • Bialvaei, (2021), Microb. Pathog., 153, pp. 104789, 10.1016/j.micpath.2021.104789
  • Maurya, (2020), Int. J. Eng. Res., V9, pp. 262
  • Farha, (2019), Nat. Microbiol., 4, pp. 565, 10.1038/s41564-019-0357-1
  • Fuchs, (2023), Proteomics, 23, pp. e2200421, 10.1002/pmic.202200421
  • Wang, F., Xiao, J., Pan, L., Yang, M., Zhang, G., Jin, S., and Yu, J. (2008). A Systematic Survey of Mini-Proteins in Bacteria and Archaea. PLoS ONE, 3.
  • Steiner, (2022), Clin. Transl. Sci., 15, pp. 2303, 10.1111/cts.13381
  • Tarasiuk, (2019), Expert Rev. Clin. Pharmacol., 12, pp. 921, 10.1080/17512433.2019.1670058
  • Aziz, (2018), Expert Opin. Drug Metab. Toxicol., 14, pp. 1043, 10.1080/17425255.2018.1530216
  • Weersma, (2020), Gut, 69, pp. 1510, 10.1136/gutjnl-2019-320204
  • Liao, C., Huang, X., Wang, Q., Yao, D., and Lu, W. (2022). Virulence Factors of Pseudomonas aeruginosa and Antivirulence Strategies to Combat Its Drug Resistance. Front. Cell. Infect. Microbiol., 12.
  • Qin, (2022), Signal Transduct. Target. Ther., 7, pp. 199, 10.1038/s41392-022-01056-1
  • Stanislavsky, (1997), FEMS Microbiol. Rev., 21, pp. 243, 10.1111/j.1574-6976.1997.tb00353.x
  • Zschiedrich, (2016), J. Mol. Biol., 428, pp. 3752, 10.1016/j.jmb.2016.08.003
  • Fadel, (2022), Structure, 30, pp. 1285, 10.1016/j.str.2022.06.002
  • Johnson, (1999), J. Mol. Biol., 287, pp. 695, 10.1006/jmbi.1999.2630
  • Abadi, (2018), Cell. Mol. Biol., 64, pp. 79, 10.14715/cmb/2018.64.13.15
  • Lorusso, A.B., Carrara, J.A., Barroso, C.D.N., Tuon, F.F., and Faoro, H. (2022). Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa. Int. J. Mol. Sci., 23.
  • Jamshidi, (2018), Sci. Rep., 8, pp. 10470, 10.1038/s41598-018-28531-6
  • Sommer, (2017), Sci. Rep., 7, pp. 5555, 10.1038/s41598-017-05621-5
  • Oliveira, W.K., Ferrarini, M., Morello, L.G., and Faoro, H. (2020). Resistome analysis of bloodstream infection bacterial genomes reveals a specific set of proteins involved in antibiotic resistance and drug efflux. NAR Genom. Bioinform., 2.
  • Alcalde-Rico, M., Olivares-Pacheco, J., Alvarez-Ortega, C., Cámara, M., and Martínez, J.L. (2018). Role of the multidrug resistance efflux pump MexCD-OprJ in the Pseudomonas aeruginosa quorum sensing response. Front. Microbiol., 9.
  • Linares, (2005), J. Bacteriol., 187, pp. 1384, 10.1128/JB.187.4.1384-1391.2005
  • Kristensen, (2024), Antimicrob. Agents Chemother., 68, pp. e0138723, 10.1128/aac.01387-23
  • Mine, (1999), Antimicrob. Agents Chemother., 43, pp. 415, 10.1128/AAC.43.2.415
  • Seupt, (2020), Antimicrob. Agents Chemother., 65, pp. e01166-20, 10.1128/AAC.01166-20
  • Poole, (1993), J. Bacteriol., 175, pp. 7363, 10.1128/jb.175.22.7363-7372.1993
  • Berman, (2000), Nucleic Acids Res., 28, pp. 235, 10.1093/nar/28.1.235
  • Yonehara, (2016), Proteins Struct. Funct. Bioinform., 84, pp. 759, 10.1002/prot.25022
  • Jumper, (2021), Nature, 596, pp. 583, 10.1038/s41586-021-03819-2
  • Greenidge, (2014), J. Chem. Inf. Model., 54, pp. 2697, 10.1021/ci5003735
  • Lans, (2019), Sci. Rep., 9, pp. 5142, 10.1038/s41598-019-41594-3
  • Bajusz, D., Rácz, A., and Héberger, K. (2019). Comparison of data fusion methods as consensus scores for ensemble docking. Molecules, 24.
  • Aron, (2016), Curr. Opin. Microbiol., 33, pp. 1, 10.1016/j.mib.2016.05.007
  • Nakashima, (2013), Nature, 500, pp. 102, 10.1038/nature12300
  • Nishino, K., Yamasaki, S., Nakashima, R., Zwama, M., and Hayashi-Nishino, M. (2021). Function and Inhibitory Mechanisms of Multidrug Efflux Pumps. Front. Microbiol., 12.
  • Murakami, (2006), Nature, 443, pp. 173, 10.1038/nature05076
  • Zwama, M., and Nishino, K. (2021). Ever-adapting rnd efflux pumps in gram-negative multidrug-resistant pathogens: A race against time. Antibiotics, 10.
  • Yáñez, O., Alegría-Arcos, M., Suardiaz, R., Morales-Quintana, L., Castro, R.I., Palma-Olate, J., Galarza, C., Catagua-González, Á., Rojas-Pérez, V., and Urra, G. (2023). Calcium-Alginate-Chitosan Nanoparticle as a Potential Solution for Pesticide Removal, a Computational Approach. Polymers, 15.
  • Salvatore, (2010), J. Pharmacol. Exp. Ther., 333, pp. 152, 10.1124/jpet.109.163816
  • Holland, (2010), Cancer Res., 70, pp. 1544, 10.1158/0008-5472.CAN-09-2997
  • Wu, (2016), Biochem. Biophys. Res. Commun., 477, pp. 861, 10.1016/j.bbrc.2016.06.149
  • (1987), Antivir. Res., 7, pp. 1, 10.1016/0166-3542(87)90034-9
  • Bateman, (2023), Nucleic Acids Res., 51, pp. D523, 10.1093/nar/gkac1052
  • Li, (2006), Bioinformatics, 22, pp. 1658, 10.1093/bioinformatics/btl158
  • Chen, (2006), Nucleic Acids Res., 34, pp. D363, 10.1093/nar/gkj123
  • Camacho, C., Coulouris, G., Avagyan, V., Ma, N., Papadopoulos, J., Bealer, K., and Madden, T.L. (2009). BLAST+: Architecture and applications. BMC Bioinform., 10.
  • Shanmugham, B., and Pan, A. (2013). Identification and Characterization of Potential Therapeutic Candidates in Emerging Human Pathogen Mycobacterium abscessus: A Novel Hierarchical In Silico Approach. PLoS ONE, 8.
  • Zhang, (2004), Nucleic Acids Res., 32, pp. D271, 10.1093/nar/gkh024
  • Chen, (2005), Nucleic Acids Res., 33, pp. D325, 10.1093/nar/gki008
  • Pal, (2014), Nucleic Acids Res., 42, pp. D737, 10.1093/nar/gkt1252
  • Doytchinova, (2007), BMC Bioinform., 8, pp. 4, 10.1186/1471-2105-8-4
  • Wishart, (2018), Nucleic Acids Res., 46, pp. D1074, 10.1093/nar/gkx1037
  • Yu, (2010), Bioinformatics, 26, pp. 1608, 10.1093/bioinformatics/btq249
  • Yu, C.-S., Cheng, C.-W., Su, W.-C., Chang, K.-C., Huang, S.-W., Hwang, J.-K., and Lu, C.-H. (2014). CELLO2GO: A Web Server for Protein subCELlular LOcalization Prediction with Functional Gene Ontology Annotation. PLoS ONE, 9.
  • Kanehisa, (2000), Nucleic Acids Res., 28, pp. 27, 10.1093/nar/28.1.27
  • Bustos, D., Hernández-Rodríguez, E.W., Castro, R.I., and Morales-Quintana, L. (2022). Structural Effects of pH Variation and Calcium Amount on the Microencapsulation of Glutathione in Alginate Polymers. Biomed Res. Int., 2022.
  • Maestro, S. (2021). Schrödinger Release 2021-1, Schrödinger LLC.
  • Roos, (2019), J. Chem. Theory Comput., 15, pp. 1863, 10.1021/acs.jctc.8b01026
  • Grant, (2021), Protein Sci., 30, pp. 20, 10.1002/pro.3923
  • Banck, (2011), J. Cheminform., 3, pp. 33, 10.1186/1758-2946-3-33
  • Corsello, (2017), Nat. Med., 23, pp. 405, 10.1038/nm.4306
  • Glavier, (2020), Nat. Commun., 11, pp. 4948, 10.1038/s41467-020-18770-5
  • Ding, (2023), J. Chem. Inf. Model., 63, pp. 1982, 10.1021/acs.jcim.2c01504
  • Wang, (2002), J. Comput. Aided Mol. Des., 16, pp. 11, 10.1023/A:1016357811882
  • Trott, (2019), J. Comput. Chem., 31, pp. 455, 10.1002/jcc.21334
  • Johnson, (2010), J. Am. Chem. Soc., 132, pp. 6498, 10.1021/ja100936w
  • Yang, (2011), J. Phys. Chem. A, 115, pp. 12983, 10.1021/jp204278k
  • Johnson, (2011), J. Chem. Theory Comput., 7, pp. 625, 10.1021/ct100641a
  • Boto, (2020), J. Chem. Theory Comput., 16, pp. 4150, 10.1021/acs.jctc.0c00063