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
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Revista:
International Journal of Molecular Sciences

ISSN: 1422-0067

Año de publicación: 2024

Volumen: 25

Número: 15

Páginas: 8027

Tipo: Artículo

DOI: 10.3390/IJMS25158027 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: International Journal of Molecular Sciences

Resumen

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.

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