New sulphonamide-peptide hybrid molecules as potential PBP 2a ligands and methicillin resistant Staphylococcus aureus actives

Abstract

Penicillin binding protein 2a (PbP 2a) expression accounts for the insusceptibility of methicillin-resistant Staphylocuccus aureus (MRSA) to β-lactam antibiotics. Here we employed computational strategies to challenge PbP 2a with series of fifty-five ‘ala-ala’ and ‘ala-pro’ sulphonamide-dipeptides. Binding stability of two compounds (labeled: 10i and 10n) with theoretical K_i in nM and µM ranges, for PbP 2a active and allosteric sites respectively, were investigated using molecular dynamics simulations. In addition, the results of the sensitivity of four strains of MRSA for compounds 10i and 10n obtained revealed the compounds at 10 µg/ml caused two isolates (S4 and S10) to revert to being susceptible. Finally, a reliable binding conformations of both compounds in the two binding sites of PbP 2a are described to provide rationale for structure-activity optimization of this series.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sulphonamides
• peptides
• PbP 2a
• MRSA
• molecular docking
• molecular dynamics simulation
• binding mode prediction

Acknowledgments

EAO received funding from CSIR-TWAS in the form of postdoctoral stay in a lab. in India. AI appreciates African-German Network Excellence in Sciences (AGNES) Junior Researchers Grant (JRG) supported by Alexander von Humboldt and sponsored by the Federal Ministry of Education and Research and postdoctoral fellowship award by The World Academy of Science; Department of Biotechnology (TWAS-DBT). The authors gratefully acknowledge funding by the Tertiary Education Trust Fund (TETFund), Nigeria [grant number: TETF/ES/DR&D- CE/NRF2020/SETI/53/VOL.1]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval and consent to participate

Not applicable.

Author contributions

Conceptualization, AI; methodology, AI, IME, EAO; formal analysis, AI, RSO, EJO, EAO; investigation, AI, RSO, EJO, EAO; resources, KR, NJN; writing—original draft preparation, AI; writing—review and editing, IME, EAO.; visualization, AI, EAO; supervision, AI, IME, KR, NJN. All authors have read and agreed to the published version of the manuscript.

Availability of data and materials

All data are available in the main manuscript.

Additional information

Funding

This research was partly sponsored by the grant from Tertiary Education Trust Fund (TETFund) Nigeria [grant number: TETF/ES/DR&D-CE/NRF/2020/SETI/53/VOL.1].