{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:39:07Z","timestamp":1784295547407,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2017,6,8]],"date-time":"2017-06-08T00:00:00Z","timestamp":1496880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chapman University School of Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u00b5g\/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 \u03b2-alanine attached to lysine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa\ufb02uorophosphate (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 \u00b5g\/mL, [R4W4K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 \u00b5g\/mL and 32 \u00b5g\/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R4W4K]-levofloxacin conjugate (MIC = 32 \u00b5g\/mL and MIC = 128 \u00b5g\/mL) and the physical mixture (MIC = 8 \u00b5g\/mL and 32 \u00b5g\/mL) was less active than levofloxacin (MIC = 2 \u00b5g\/mL and 4 = \u00b5g\/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.<\/jats:p>","DOI":"10.3390\/molecules22060957","type":"journal-article","created":{"date-parts":[[2017,6,8]],"date-time":"2017-06-08T10:26:09Z","timestamp":1496917569000},"page":"957","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Synthesis and Evaluation of Antimicrobial Activity of [R4W4K]-Levofloxacin and [R4W4K]-Levofloxacin-Q Conjugates"],"prefix":"10.3390","volume":"22","author":[{"given":"Neda","family":"Riahifard","sequence":"first","affiliation":[{"name":"Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Tavakoli","sequence":"additional","affiliation":[{"name":"Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Yamaki","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8600-0893","authenticated-orcid":false,"given":"Keykavous","family":"Parang","sequence":"additional","affiliation":[{"name":"Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,6,8]]},"reference":[{"key":"ref_1","first-page":"226","article-title":"On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenz\u00e6","volume":"10","author":"Fleming","year":"1929","journal-title":"Br. 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