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 µg/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 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 [R4W4K]-levofloxacin-Q and [R4W4K]-levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 µg/mL, [R4W4K]-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, [R4W4K]-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 [R4W4K] significantly reduced the antibacterial activity compared to the parent analogs, while [R4W4K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone.
Highlights
The discovery of penicillin [1,2] and streptomycin [3] and other antibiotics led to the treatment of a number of prevalent microbial diseases
Combination of existing antibiotics to enhance activity the of antibioticsdevelopment and antimicrobial cationic peptide improves bactericidal against efficacy are among the suitable strategies
Our laboratory has previously reported that the amphiphilic cyclic peptide [R4 W4 ] (3), a cell-penetrating peptide (CPP) (Figure 1) containing arginine (R) and tryptophan (W) residues has antibacterial activity with minimum inhibitory concentration (MIC) value of 2.97 μg/mL against Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant bacterium commonly found in the hospital and community settings [25]
Summary
The discovery of penicillin [1,2] and streptomycin [3] and other antibiotics led to the treatment of a number of prevalent microbial diseases. The decline in the numbers of marketed antibiotics was mainly due to the difficulty of compounds to penetrate bacterial cells [6] and high costs related to drug-development [7]. Modification, conjugation or combination of existing antibiotics to enhance the efficacy are among the suitable strategies. Combination approaches have been applied to demonstrate improved antimicrobial therapy [10]. A cationic antimicrobial peptide, arenicin-1, was able to enhance fluoroquinolone entry into the bacterial cytoplasmic membrane [11]. Modification, conjugation or brevinin-2CE combination of existing antibiotics to enhance activity the of antibioticsdevelopment and antimicrobial cationic peptide improves bactericidal against efficacy are among the suitable strategies. Modification of known antibiotics has been used to improve multidrug-resistant bacteria [12]
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