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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...

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Autores principales: Biswal, Sarmistha, Caetano, Karina, Jain, Diamond, Sarrila, Anusha, Munshi, Tulika, Dickman, Rachael, Tabor, Alethea B., Rath, Surya Narayan, Bhakta, Sanjib, Ghosh, Anindya S.
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
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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.
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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
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