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Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates
The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152667/ https://www.ncbi.nlm.nih.gov/pubmed/28594345 http://dx.doi.org/10.3390/molecules22060957 |
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author | Riahifard, Neda Tavakoli, Kathy Yamaki, Jason Parang, Keykavous Tiwari, Rakesh |
author_facet | Riahifard, Neda Tavakoli, Kathy Yamaki, Jason Parang, Keykavous Tiwari, Rakesh |
author_sort | Riahifard, Neda |
collection | PubMed |
description | The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R(4)W(4)] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 µg/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R(4)W(4)] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to synthesize conjugates of [R(4)W(4)K]-levofloxacin-Q and [R(4)W(4)K]-levofloxacin. The carboxylic acid group of levofloxacin or levofloxacin-Q was conjugated with the amino group of β-alanine attached to lysine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) for 3 h to afford the products. Antibacterial assays were conducted to determine the potency of conjugates [R(4)W(4)K]-levofloxacin-Q and [R(4)W(4)K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 µg/mL, [R(4)W(4)K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 µg/mL and 32 µg/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R(4)W(4)K]-levofloxacin conjugate (MIC = 32 µg/mL and MIC = 128 µg/mL) and the physical mixture (MIC = 8 µg/mL and 32 µg/mL) was less active than levofloxacin (MIC = 2 µg/mL and 4 = µg/mL) against MRSA and Klebsiella pneumoniae, respectively. The data showed that the conjugation of levofloxacin with [R(4)W(4)K] significantly reduced the antibacterial activity compared to the parent analogs, while [R(4)W(4)K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone. |
format | Online Article Text |
id | pubmed-6152667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61526672018-11-13 Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates Riahifard, Neda Tavakoli, Kathy Yamaki, Jason Parang, Keykavous Tiwari, Rakesh Molecules Article The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R(4)W(4)] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 µg/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R(4)W(4)] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to synthesize conjugates of [R(4)W(4)K]-levofloxacin-Q and [R(4)W(4)K]-levofloxacin. The carboxylic acid group of levofloxacin or levofloxacin-Q was conjugated with the amino group of β-alanine attached to lysine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) for 3 h to afford the products. Antibacterial assays were conducted to determine the potency of conjugates [R(4)W(4)K]-levofloxacin-Q and [R(4)W(4)K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 µg/mL, [R(4)W(4)K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 µg/mL and 32 µg/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R(4)W(4)K]-levofloxacin conjugate (MIC = 32 µg/mL and MIC = 128 µg/mL) and the physical mixture (MIC = 8 µg/mL and 32 µg/mL) was less active than levofloxacin (MIC = 2 µg/mL and 4 = µg/mL) against MRSA and Klebsiella pneumoniae, respectively. The data showed that the conjugation of levofloxacin with [R(4)W(4)K] significantly reduced the antibacterial activity compared to the parent analogs, while [R(4)W(4)K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone. MDPI 2017-06-08 /pmc/articles/PMC6152667/ /pubmed/28594345 http://dx.doi.org/10.3390/molecules22060957 Text en © 2017 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 Riahifard, Neda Tavakoli, Kathy Yamaki, Jason Parang, Keykavous Tiwari, Rakesh Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title | Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title_full | Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title_fullStr | Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title_full_unstemmed | Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title_short | Synthesis and Evaluation of Antimicrobial Activity of [R(4)W(4)K]-Levofloxacin and [R(4)W(4)K]-Levofloxacin-Q Conjugates |
title_sort | synthesis and evaluation of antimicrobial activity of [r(4)w(4)k]-levofloxacin and [r(4)w(4)k]-levofloxacin-q conjugates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152667/ https://www.ncbi.nlm.nih.gov/pubmed/28594345 http://dx.doi.org/10.3390/molecules22060957 |
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