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Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents

There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential...

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Autores principales: Yu, Tsz Tin, Kuppusamy, Rajesh, Yasir, Muhammad, Hassan, Md. Musfizur, Alghalayini, Amani, Gadde, Satyanarayana, Deplazes, Evelyne, Cranfield, Charles, Willcox, Mark D.P., Black, David StC, Kumar, Naresh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555970/
https://www.ncbi.nlm.nih.gov/pubmed/32947921
http://dx.doi.org/10.3390/ijms21186789
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author Yu, Tsz Tin
Kuppusamy, Rajesh
Yasir, Muhammad
Hassan, Md. Musfizur
Alghalayini, Amani
Gadde, Satyanarayana
Deplazes, Evelyne
Cranfield, Charles
Willcox, Mark D.P.
Black, David StC
Kumar, Naresh
author_facet Yu, Tsz Tin
Kuppusamy, Rajesh
Yasir, Muhammad
Hassan, Md. Musfizur
Alghalayini, Amani
Gadde, Satyanarayana
Deplazes, Evelyne
Cranfield, Charles
Willcox, Mark D.P.
Black, David StC
Kumar, Naresh
author_sort Yu, Tsz Tin
collection PubMed
description There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.
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spelling pubmed-75559702020-10-19 Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents Yu, Tsz Tin Kuppusamy, Rajesh Yasir, Muhammad Hassan, Md. Musfizur Alghalayini, Amani Gadde, Satyanarayana Deplazes, Evelyne Cranfield, Charles Willcox, Mark D.P. Black, David StC Kumar, Naresh Int J Mol Sci Article There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages. MDPI 2020-09-16 /pmc/articles/PMC7555970/ /pubmed/32947921 http://dx.doi.org/10.3390/ijms21186789 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yu, Tsz Tin
Kuppusamy, Rajesh
Yasir, Muhammad
Hassan, Md. Musfizur
Alghalayini, Amani
Gadde, Satyanarayana
Deplazes, Evelyne
Cranfield, Charles
Willcox, Mark D.P.
Black, David StC
Kumar, Naresh
Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title_full Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title_fullStr Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title_full_unstemmed Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title_short Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents
title_sort design, synthesis and biological evaluation of biphenylglyoxamide-based small molecular antimicrobial peptide mimics as antibacterial agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555970/
https://www.ncbi.nlm.nih.gov/pubmed/32947921
http://dx.doi.org/10.3390/ijms21186789
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