Exploring the Potential of Designed Peptides Containing Lysine and Arginine Repeats against VIM-2 Metallo-Beta-Lactamases

• Published in: International journal of peptide research and therapeutics 2024-06, Vol.30 (4), p.41, Article 41
• Main Authors: Anurag Anand, Ananya, Sahoo, Amaresh Kumar, Samanta, Sintu Kumar
• Format: Article
• Language: English
• Subjects: Affinity; Animal Anatomy; Antibiotics; Arginine; Biochemistry; Biomedical and Life Sciences; Histology; Life Sciences; Lysine; Metallo-β-lactamase; Molecular Medicine; Morphology; Peptides; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Polymer Sciences; Public health; Toxicity; β-Lactam antibiotics
• ISSN: 1573-3904; 1573-3149; 1573-3904
• DOI: 10.1007/s10989-024-10619-5

The persistent development of bacterial resistance to β-lactam antibiotics presents a serious risk to public health worldwide. The ability of metallo-β-lactamases (MBLs) to hydrolyze a wide range of β-lactam antibiotics and render them ineffective makes them a difficult challenge. The identification and design of clinically useful inhibitors against MBLs like Verona integron-encoded metallo-β-lactamase-2 (VIM-2) is still challenging. In this study, we examine the inhibitory capacity of peptides against VIM-2 of Pseudomonas aeruginosa . Deriving inspiration from earlier studies on arginine-rich peptides, we hypothesized that lysine repeats with similar nature may show comparable binding with VIM-2.We found that lysine repeats are much more stable than arginine repeats, and show comparable binding with VIM-2. Initially, we designed a library of peptides containing various combinations of lysine and arginine residues, with the sequence length of 30 amino acids. By means of computational modeling, Protein-Peptide docking and molecular dynamics simulations, we evaluated the stability and binding affinity of these peptides in complex with VIM-2. Peptides showing best binding with VIM-2 were subjected to optimization where length was reduced to 12 residues. This optimization was performed to reduce charge and potential toxicity, enhancing the translational prospects of the sequences. We observed that PolyKR (6) was found to be the lead candidate. We demonstrate that incorporation of KR repeats in peptide sequences can be of help in enhancing their binding affinity towards VIM-2. Further, wet-laboratory validation needs to be performed in order to study the interaction of the peptide with the VIM-2 MBL in detail.