Document Type
Article
Publication Date
6-8-2017
Abstract
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 [R4W4] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 g/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R4W4] 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 [R4W4K]-levofloxacin-Q and [R4W4K]-levofloxacin. The carboxylic acid group of levofloxacin or levofloxacin-Q was conjugated with the amino group of -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 [R4W4K]-levofloxacin-Q and [R4W4K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 g/mL, [R4W4K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 g/mL and 32 g/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R4W4K]-levofloxacin conjugate (MIC = 32 g/mL and MIC = 128 g/mL) and the physical mixture (MIC = 8 g/mL and 32 g/mL) was less active than levofloxacin (MIC = 2 g/mL and 4 = g/mL) against MRSA and Klebsiella pneumoniae, respectively. The data showed that the conjugation of levofloxacin with [R4W4K] significantly reduced the antibacterial activity compared to the parent analogs, while [R4W4K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone.
Recommended Citation
Riahifard N, Tavakoli K, Yamaki J, Parang K, Tiwari R. Synthesis and Evaluation of Antimicrobial Activity of [R4W4K]-Levofloxacin and [R4W4K]-Levofloxacin-Q Conjugates. Molecules. 2017; 22(6):957. doi:10.3390/molecules22060957
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The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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Amino Acids, Peptides, and Proteins Commons, Chemical Actions and Uses Commons, Medicinal and Pharmaceutical Chemistry Commons, Other Chemicals and Drugs Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutical Preparations Commons, Virus Diseases Commons
Comments
This article was originally published in Molecules, volume 22, issue 6, in 2017. DOI: 10.3390/molecules22060957