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Synthesis and Evaluation of Antimicrobial Activity of [R?W?K]-Levofloxacin and [R?W?K]-Levofloxacin-Q Conjugates.

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 [R?W?] 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?W?] 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?W?K]-levofloxacin-Q and [R?W?K]-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 hexa?uorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) for 3 h to afford the products. Antibacterial assays were conducted to determine the potency of conjugates [R?W?K]-levofloxacin-Q and [R?W?K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 µg/mL, [R?W?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?W?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?W?K] significantly reduced the antibacterial activity compared to the parent analogs, while [R?W?K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone.

SUBMITTER: Riahifard N

PROVIDER: S-EPMC6152667 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Synthesis and Evaluation of Antimicrobial Activity of [R₄W₄K]-Levofloxacin and [R₄W₄K]-Levofloxacin-Q Conjugates.

Riahifard Neda N Tavakoli Kathy K Yamaki Jason J Parang Keykavous K Tiwari Rakesh R

Molecules (Basel, Switzerland) 20170608 6

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 µg/mL against Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Her ...[more]

PMID: 28594345

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Dataset Information

Synthesis and Evaluation of Antimicrobial Activity of [R?W?K]-Levofloxacin and [R?W?K]-Levofloxacin-Q Conjugates.

Publications

Synthesis and Evaluation of Antimicrobial Activity of [R₄W₄K]-Levofloxacin and [R₄W₄K]-Levofloxacin-Q Conjugates.

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