Novel antimicrobial peptide HFIAP-1 mutant as a β-lactamase inhibitor against extended-spectrum β-lactamases of Escherichia coli: a comprehensive in-silico approach

Abstract

Extended-spectrum β-lactamases in Escherichia coli poses a significant threat for clinicians in tertiary healthcare settings, rendering treatments ineffective with newer β-lactam-β-lactamase inhibitors combinations. To overcome this, the present study was conducted to potential β-lactamase inhibitors, from a library of antimicrobial peptide mutants with enhanced antibacterial potency (~ 7–16%) as compared to their parent peptides. The study screened five peptides and their mutants based on physicochemical, pharmaco-immunogenic properties through comprehensive knowledge-based and machine-learning algorithms. Molecular docking analyses revealed HFIAP-1_M5 (L33K-W7C-N34C) as the potential inhibitor candidate, that predicted to inhibit ~ 82% of all the studied ESβLs (Class A–D) targets as analysed from the intermolecular interaction profiling. HFIAP-1_M5 exhibited enhanced binding affinities (~ 0.2–12.0%) than the parent peptides upon forming hydrogen bonds, van-der Waals interactions and salt bridges with crucial residues concerning the catalytic domains of class A [InterPro ID: IPR045155], class B [InterPro ID: IPR001279], class C [InterPro ID: IPR001466] and class D [InterPro ID: IPR001460] of β-lactamases as defined in the InterPro database. All-atom molecular dynamics simulations, supported by principal component analysis and free energy landscape analysis, confirmed the stability of ESβLs-HFIAP-1_M5 showing stable backbone profiles with minimal residue-level fluctuations throughout the simulation timeframe. Binding free energy calculations along with the energy decomposition analysis further highlighted the key residue contributions to complex stabilization. The study holds promise in developing a combination therapy upon augmenting HFIAP-1_M5 with susceptible β-lactam antibiotics to enhance the therapeutic spectrum of treatment after further experimental validations.