Peptide conjugates of lactoferricin analogues and antimicrobials—Design, chemical synthesis, and evaluation of antimicrobial activity and mammalian cytotoxicity

Ptaszyńska, Natalia; Olkiewicz, Katarzyna; Okońska, Joanna; Gucwa, Katarzyna; Łęgowska, Anna; Gitlin-Domagalska, Agata; Dębowski, Dawid; Lica, Jan; Heldt, Mateusz; Milewski, Sławomir; Ng, Tzi Bun; Rolka, Krzysztof

doi:10.1016/j.peptides.2019.04.006

Cited by 17 publications

(23 citation statements)

References 32 publications

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“…The antibacterial activity (bacteriostatic: MIC and bactericidal: MBC) of the tested compounds was determined in MHB (Mueller Hinton Broth, Sigma Aldrich, St. Louis, MO, USA) using a serial two-fold dilution method in 96-well microtiter plates according to CLSI recommendations, described in M07-A10 document. The exact conditions have been described previously [9]. All experiments were performed in three replicates.…”

Section: Antibacterial Activity Assaymentioning

confidence: 99%

“…The only example of similar derivatisation of fluoroquinolones was enrofloxacin and ciprofloxacin conjugates with β-octaarginine, showing a similar or lower in vitro antibacterial potential than the mother chemotherapeutics [ 8 ]. On the other hand, in our previous studies, we demonstrated some beneficial results of the conjugation of CIP and LVX with antimicrobial peptides (AMPs), namely the lactoferricin truncated analogues [ 9 ] and lactoferrin HLopt2 fragment [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Conjugates of Ciprofloxacin and Levofloxacin with Cell-Penetrating Peptide Exhibit Antifungal Activity and Mammalian Cytotoxicity

Ptaszyńska

Gucwa

Olkiewicz

et al. 2020

IJMS

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Seven conjugates composed of well-known fluoroquinolone antibacterial agents, ciprofloxacin (CIP) or levofloxacin (LVX), and a cell-penetrating peptide transportan 10 (TP10-NH2) were synthesised. The drugs were covalently bound to the peptide via an amide bond, methylenecarbonyl moiety, or a disulfide bridge. Conjugation of fluoroquinolones to TP10-NH2 resulted in congeners demonstrating antifungal in vitro activity against human pathogenic yeasts of the Candida genus (MICs in the 6.25–100 µM range), whereas the components were poorly active. The antibacterial in vitro activity of most of the conjugates was lower than the activity of CIP or LVX, but the antibacterial effect of CIP-S-S-TP10-NH2 was similar to the mother fluoroquinolone. Additionally, for two representative CIP and LVX conjugates, a rapid bactericidal effect was shown. Compared to fluoroquinolones, TP10-NH2 and the majority of its conjugates generated a relatively low level of reactive oxygen species (ROS) in human embryonic kidney cells (HEK293) and human myeloid leukemia cells (HL-60). The conjugates exhibited cytotoxicity against three cell lines, HEK293, HepG2 (human liver cancer cell line), and LLC-PK1 (old male pig kidney cells), with IC50 values in the 10–100 µM range and hemolytic activity. The mammalian toxicity was due to the intrinsic cytoplasmic membrane disruption activity of TP10-NH2 since fluoroquinolones themselves were not cytotoxic. Nevertheless, the selectivity index values of the conjugates, both for the bacteria and human pathogenic yeasts, remained favourable.

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Section: Antibacterial Activity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Conjugates of Ciprofloxacin and Levofloxacin with Cell-Penetrating Peptide Exhibit Antifungal Activity and Mammalian Cytotoxicity

Ptaszyńska

Gucwa

Olkiewicz

et al. 2020

IJMS

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“…All conjugates were synthesized according to the methodology described previously [26,30]. In the case of conjugates 2 and 4, CIP and LVX were manually added to the peptidyl resin.…”

Section: Citropin Analogsmentioning

confidence: 99%

“…This procedure was repeated until the chloranil test gave a negative result. To synthesize conjugate 2, the submonomeric approach [30] was utilized. In the first step, bromoacetic acid and DIC (5 equiv.…”

Section: Citropin Analogsmentioning

confidence: 99%

Can Immobilized Artificial Membrane Chromatography Support the Characterization of Antimicrobial Peptide Origin Derivatives?

et al. 2021

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The emergence and spread of multiple drug-resistant bacteria strains caused the development of new antibiotics to be one of the most important challenges of medicinal chemistry. Despite many efforts, the commercial availability of peptide-based antimicrobials is still limited. The presented study aims to explain that immobilized artificial membrane chromatography can support the characterization of antimicrobial peptides. Consequently, the chromatographic experiments of three groups of related peptide substances: (i) short cationic lipopeptides, (ii) citropin analogs, and (iii) conjugates of ciprofloxacin and levofloxacin, with a cell-penetrating peptide were discussed. In light of the discussion of the mechanisms of action of these compounds, the obtained results were interpreted.

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“…26 Through the strategy called conjugation, it is possible to obtain new entities from the union of sequences derived from AMPs such as buforin and LfcinB with other antimicrobial molecules, with the aim of enhancing their antibacterial activity. 27,28 In the present investigation, sequences derived from buforin (RLLR, RLLRLLR) and LfcinB (RRWQWR, RWQWRWQWR) were synthesized by means of SPPS Fmoc/tBu and conjugated with non-peptidic organic molecules such as 6aminohexanoic acid (Ahx), ferrocene (Fc), caffeic acid (CA), ferulic acid (FA), and oxolinic acid (OA) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Short peptides conjugated to non-peptidic motifs exhibit antibacterial activity

et al. 2020

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Peptide conjugates of lactoferricin analogues and antimicrobials—Design, chemical synthesis, and evaluation of antimicrobial activity and mammalian cytotoxicity

Cited by 17 publications

References 32 publications

Conjugates of Ciprofloxacin and Levofloxacin with Cell-Penetrating Peptide Exhibit Antifungal Activity and Mammalian Cytotoxicity

Conjugates of Ciprofloxacin and Levofloxacin with Cell-Penetrating Peptide Exhibit Antifungal Activity and Mammalian Cytotoxicity

Can Immobilized Artificial Membrane Chromatography Support the Characterization of Antimicrobial Peptide Origin Derivatives?

Short peptides conjugated to non-peptidic motifs exhibit antibacterial activity

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