Cargando…
Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics
Class A serine β-lactamases (SBLs) have a conserved non-active site structural domain called the omega loop (Ω-loop), in which a glutamic acid residue is believed to be directly involved in the hydrolysis of β-lactam antibiotics by providing a water molecule during catalysis. We aimed to design and...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10044640/ https://www.ncbi.nlm.nih.gov/pubmed/36978420 http://dx.doi.org/10.3390/antibiotics12030553 |
_version_ | 1784913394874187776 |
---|---|
author | Biswal, Sarmistha Caetano, Karina Jain, Diamond Sarrila, Anusha Munshi, Tulika Dickman, Rachael Tabor, Alethea B. Rath, Surya Narayan Bhakta, Sanjib Ghosh, Anindya S. |
author_facet | Biswal, Sarmistha Caetano, Karina Jain, Diamond Sarrila, Anusha Munshi, Tulika Dickman, Rachael Tabor, Alethea B. Rath, Surya Narayan Bhakta, Sanjib Ghosh, Anindya S. |
author_sort | Biswal, Sarmistha |
collection | PubMed |
description | Class A serine β-lactamases (SBLs) have a conserved non-active site structural domain called the omega loop (Ω-loop), in which a glutamic acid residue is believed to be directly involved in the hydrolysis of β-lactam antibiotics by providing a water molecule during catalysis. We aimed to design and characterise potential pentapeptides to mask the function of the Ω-loop of β-lactamases and reduce their efficacy, along with potentiating the β-lactam antibiotics and eventually decreasing β-lactam resistance. Considering the Ω-loop sequence as a template, a group of pentapeptide models were designed, validated through docking, and synthesised using solid-phase peptide synthesis (SPPS). To check whether the β-lactamases (BLAs) were inhibited, we expressed specific BLAs (TEM-1 and SHV-14) and evaluated the trans-expression through a broth dilution method and an agar dilution method (HT-SPOTi). To further support our claim, we conducted a kinetic analysis of BLAs with the peptides and employed molecular dynamics (MD) simulations of peptides. The individual presence of six histidine-based peptides (TSHLH, ETHIH, ESRLH, ESHIH, ESRIH, and TYHLH) reduced β-lactam resistance in the strains harbouring BLAs. Subsequently, we found that the combinational effect of these peptides and β-lactams sensitised the bacteria towards the β-lactam drugs. We hypothesize that the antimicrobial peptides obtained might be considered among the novel inhibitors that can be used specifically against the Ω-loop of the β-lactamases. |
format | Online Article Text |
id | pubmed-10044640 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100446402023-03-29 Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics Biswal, Sarmistha Caetano, Karina Jain, Diamond Sarrila, Anusha Munshi, Tulika Dickman, Rachael Tabor, Alethea B. Rath, Surya Narayan Bhakta, Sanjib Ghosh, Anindya S. Antibiotics (Basel) Article Class A serine β-lactamases (SBLs) have a conserved non-active site structural domain called the omega loop (Ω-loop), in which a glutamic acid residue is believed to be directly involved in the hydrolysis of β-lactam antibiotics by providing a water molecule during catalysis. We aimed to design and characterise potential pentapeptides to mask the function of the Ω-loop of β-lactamases and reduce their efficacy, along with potentiating the β-lactam antibiotics and eventually decreasing β-lactam resistance. Considering the Ω-loop sequence as a template, a group of pentapeptide models were designed, validated through docking, and synthesised using solid-phase peptide synthesis (SPPS). To check whether the β-lactamases (BLAs) were inhibited, we expressed specific BLAs (TEM-1 and SHV-14) and evaluated the trans-expression through a broth dilution method and an agar dilution method (HT-SPOTi). To further support our claim, we conducted a kinetic analysis of BLAs with the peptides and employed molecular dynamics (MD) simulations of peptides. The individual presence of six histidine-based peptides (TSHLH, ETHIH, ESRLH, ESHIH, ESRIH, and TYHLH) reduced β-lactam resistance in the strains harbouring BLAs. Subsequently, we found that the combinational effect of these peptides and β-lactams sensitised the bacteria towards the β-lactam drugs. We hypothesize that the antimicrobial peptides obtained might be considered among the novel inhibitors that can be used specifically against the Ω-loop of the β-lactamases. MDPI 2023-03-10 /pmc/articles/PMC10044640/ /pubmed/36978420 http://dx.doi.org/10.3390/antibiotics12030553 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Biswal, Sarmistha Caetano, Karina Jain, Diamond Sarrila, Anusha Munshi, Tulika Dickman, Rachael Tabor, Alethea B. Rath, Surya Narayan Bhakta, Sanjib Ghosh, Anindya S. Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title | Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title_full | Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title_fullStr | Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title_full_unstemmed | Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title_short | Antimicrobial Peptides Designed against the Ω-Loop of Class A β-Lactamases to Potentiate the Efficacy of β-Lactam Antibiotics |
title_sort | antimicrobial peptides designed against the ω-loop of class a β-lactamases to potentiate the efficacy of β-lactam antibiotics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10044640/ https://www.ncbi.nlm.nih.gov/pubmed/36978420 http://dx.doi.org/10.3390/antibiotics12030553 |
work_keys_str_mv | AT biswalsarmistha antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT caetanokarina antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT jaindiamond antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT sarrilaanusha antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT munshitulika antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT dickmanrachael antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT taboraletheab antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT rathsuryanarayan antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT bhaktasanjib antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics AT ghoshanindyas antimicrobialpeptidesdesignedagainsttheōloopofclassablactamasestopotentiatetheefficacyofblactamantibiotics |