Evaluation of The Efficacy of Ceftaroline and Ceftobiprole Against PBP2a in Methicillin-Resistant Staphylococcus aureus: New Insights from Molecular Modeling
الموضوعات :
1 - Ph.D. Microbiology, Department of Anatomy, College of Medicine, University of Mosul, Mosul, Iraq
الکلمات المفتاحية: Ceftaroline, Ceftobiprole, Staphylococcus aureus, Docking, PBP2a ,
ملخص المقالة :
Penicillin-Binding Protein 2a (PBP2a) is the primary cause of bacterial resistance to beta-lactam antibiotics such as methicillin. PBP2a mutations produce structural alterations that reduce the antibiotic's efficacy. Fifth-generation antibiotics, such as ceftaroline and ceftobizole, have a high affinity for binding to PBP2a, making them effective treatments for resistant Staphylococcus aureus. The purpose of this study was to assess the influence of PBP2a mutations and the efficacy of ceftaroline fosamil and ceftobiprole when administered in combination as a novel therapeutic approach utilizing current molecular models. RCSB PDB data were utilized to select the wild-type strain 1VQQ and the mutant 4CJN, as well as to examine their mutations (E246G, N146K, N204K) in three dimensions using PyMol. The effect of the changes on binding energy was assessed using mCSM-PPI2 and mCSM-AB methods, and molecular docking simulations of ceftaroline and ceftobiprole were carried out using PyRx and AutodockVina to determine binding energy and active sites. The findings revealed that the bulk of mutations, including E246G, E239K, and N146K, decreased protein affinity, whereas mutation N204K increased affinity. Molecular research revealed that coadministration of ceftaroline and ceftobifole considerably reduced ceftaroline efficacy, while ceftobiprole efficacy was only slightly raised or unaffected in both wild-type and mutant strains. These findings point to an overlapping action between the two antagonists at the active and inactive locations. The combination of ceftaroline and ceftobiprol has adverse effects on antibiotic binding to PBP2a, confirming that they cannot be administered effectively together.
1. Lim D., Strynadka N.C., 2002. Structural Basis for the β-Lactam Resistance of PBP2a from Methicillin-Resistant Staphylococcus aureus. Nature Structural Biology. 9 (11), 870–876.
2. Ito T., Katayama Y., Hiramatsu K., 2001. Structural Comparison of Three Types of Staphylococcal Cassette Chromosome mec Integrated in the Chromosome in Methicillin-Resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 45(5), 1323–1336.
3. Clinical and Laboratory Standards Institute (CLSI), 2023. Performance Standards for Antimicrobial Susceptibility Testing; CLSI Supplement M100, 33rd ed. CLSI.
4. Fishovitz J., Hermoso J.A., Chang M, Mobashery S., 2014. The Covalent Ceftaroline-PBP2a Complex: A New Paradigm for β-Lactam Inhibition. Journal of Molecular Biology. 426(14), 2579–2595.
5. International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-SCC), 2009. Staphylococcal Cassette Chromosome mec (SCCmec) Classification and Typing Methods. Antimicrobial Agents and Chemotherapy. 53(12), 4961–4967.
6. Otero L.H., Rojas-Altuve A., Llarrull L.I., Carrasco-López C., Kumarasiri M., Lastochkin E., 2013. How Allosteric Control of Staphylococcus aureus Penicillin-Binding Protein 2a Enables Methicillin Resistance and Physiological Function. Proceedings of the National Academy of Sciences of the United States of America. 110(42), 16808–16813.
7. Llarrull L.I., Fisher J.F., Mobashery S., 2010. The Future of the β-Lactams. Current Opinion in Microbiology. 13(5), 551–557.
8. World Health Organization (WHO), 2022. Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report. WHO.
9. Fishovitz J., Hermoso J.A., Chang M., Mobashery S., 2014. Ceftaroline Resistance in Staphylococcus aureus is Mediated by the Novel PBP2a Variant Encoded by mecC. Antimicrobial Agents and Chemotherapy. 58(9), 5263–5271.
10. RCSB Protein Data Bank, 2019. PBP2a in Complex with Ceftaroline. PDB ID: 6Q9N.
11. Peacock S.J., Paterson G.K., 2015. Methicillin Resistance in Staphylococcus aureus: Mechanisms and Modulation. Nature Reviews Microbiology. 13(1), 42–51.
12. Deurenberg R.H., Vink C., Kalenic S., Friedrich A.W., Bruggeman C.A., Stobberingh E.E., 2007. The Evolutionary History of Methicillin-Resistant Staphylococcus aureus (MRSA). Proceedings of the National Academy of Sciences of the United States of America. 104(23), 9457–9462.
13. Long S.W., Olsen R.J., Mehta S.C., Palzkill T., Cernoch P.L., Perez K.K., 2014. PBP2a Mutations Causing High-Level Ceftaroline Resistance in Clinical Methicillin-Resistant Staphylococcus aureus Isolates. Antimicrobial Agents and Chemotherapy. 58(11), 6668–6674.
14. Lodise T.P., Low D.E., 2012. Ceftaroline Fosamil in the Treatment of Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections. Drugs. 72(11), 1473–1493.
15. Noel G.J., Bush K., Bagchi P., Ianus J., Strauss R.S., 2008. A Randomized, Double-Blind Trial Comparing Ceftobiprole Medocaril with Vancomycin Plus Ceftazidime for the Treatment of Patients with Complicated Skin and Skin-Structure Infections. Clinical Infectious Diseases. 46(5), 647–655.
16. Livermore D.M., 2006. Can Beta-Lactams Be Re-Engineered to Beat MRSA? Clinical Microbiology and Infection. 12(Suppl 2), 11–16.
17. Rodrigues C.H.M., Myung Y., Pires D.E., Ascher D.B., 2019. mCSM-PPI2: Predicting the Effects of Mutations on Protein–Protein Interactions. Nucleic Acids Research. 47(W1), W338–W344.
18. Ammar A., Cavill R., Evelo C., Willighagen E., 2023. PSnpBind-ML: Predicting the Effect of Binding Site Mutations on Protein-Ligand Binding Affinity. Journal of Cheminformatics. 15(31). https://doi.org/10.1186/s13321-023-00701-3.
19. Xiao S.R., Zhang Y.K., Liu K.Y., Huang Y.X., Liu R., 2024. PNBACE: An Ensemble Algorithm to Predict the Effects of Mutations on Protein-Nucleic Acid Binding Affinity. BMC Biology. 22(203). https://doi.org/10.1186/s12915-024-02006-9
20. Nikam R., Jemimah S., Gromiha M.M., 2024. DeepPPAPredMut: Deep Ensemble Method for Predicting the Binding Affinity Change in Protein–Protein Complexes upon Mutation. Bioinformatics. 40(5). https://doi.org/10.1093/bioinformatics/btae309
21. Dudhat K., 2023. Panoramic Review on Progress and Development of Molecular Docking. Pharmaceutical Science & Technology. 7(1), 1–4.
22. RCSB Protein Data Bank, 2010. PBP2a from Staphylococcus aureus. PDB ID: 3ZG8.
23. Sundaram A., Chen C., Mousa J.J., Hu Y., Sause W.E., Kumar R., 2022. Single-Domain Antibodies Targeting Staphylococcus aureus PBP2a Reverse β-Lactam Resistance. Nature Communications. 13(1), 2059.
24. ClinicalTrials.gov, 2023. Study of AR-301 in Adults with Ventilator-Associated Pneumonia Caused by S. aureus. Identifier: NCT03131573.
25. ClinicalTrials.gov., 2022. A Study of MEDI4893 in Adults Hospitalized with Pneumonia. Identifier: NCT02296320.
26. Amani A., Alayash F.M., Abed F.M., 2024. The Novel Genomic DNA Integrity in Neutral Buffer Formalin, Bouin’s Fluid, and Zinc Formalin Fixatives: A Comparative Study. Iraqi Journal of Veterinary Sciences. 38(3), 715–719.
27. Dawood A.A., 2024. Designing an Immuno-Epitope Candidate Vaccine from (Opa, ProA, ProB, RmpM, and BamD) Proteins Against Neisseria gonorrhoeae and Neisseria meningitidis. Vacunas. 25(4), 481–491.
28. Dawood A.A., 2024. A Method Utilizing an Image Visibility Graph to Portray the Arrangement of Genomic Data Sequencing, Gene Frequencies for The Peptidoglycan-Associated Lipoprotein (Pal) Gene in Brucella spp., and Prevalence of Brucellosis in Nineveh. Medicina Moderna. 31(2), 155–165.
