Modification of Dispersin B with Cyclodextrin-Ciprofloxacin Derivatives for Treating Staphylococcal

Jinan Abdelkader; Magbool Alelyani; Yazeed Alashban; Sami A Alghamdi; Youssef Bakkour

doi:10.3390/molecules28145311

Modification of Dispersin B with Cyclodextrin-Ciprofloxacin Derivatives for Treating Staphylococcal

Molecules. 2023 Jul 10;28(14):5311. doi: 10.3390/molecules28145311.

Authors

Jinan Abdelkader¹, Magbool Alelyani², Yazeed Alashban³, Sami A Alghamdi³, Youssef Bakkour²

Affiliations

¹ Laboratory of Applied Chemistry (LAC), Department of Chemistry, Faculty of Sciences III, Lebanese University Mont Michel, El Koura 826, Lebanon.
² Department of Radiological Sciences, College of Applied Medical Science, King Khalid University, Abha 61421, Saudi Arabia.
³ Radiological Sciences Department, College of Applied Medical Sciences, King Saud University, P.O. Box 145111, Riyadh 4545, Saudi Arabia.

Abstract

To address the high tolerance of biofilms to antibiotics, it is urgent to develop new strategies to fight against these bacterial consortia. An innovative antibiofilm nanovector drug delivery system, consisting of Dispersin B-permethylated-β-cyclodextrin/ciprofloxacin adamantyl (DspB-β-CD/CIP-Ad), is described here. For this purpose, complexation assays between CIP-Ad and (i) unmodified β-CD and (ii) different derivatives of β-CD, which are 2,3-O-dimethyl-β-CD, 2,6-O-dimethyl-β-CD, and 2,3,6-O-trimethyl-β-CD, were tested. A stoichiometry of 1/1 was obtained for the β-CD/CIP-Ad complex by NMR analysis. Isothermal Titration Calorimetry (ITC) experiments were carried out to determine Ka, ΔH, and ΔS thermodynamic parameters of the complex between β-CD and its different derivatives in the presence of CIP-Ad. A stoichiometry of 1/1 for β-CD/CIP-Ad complexes was confirmed with variable affinity according to the type of methylation. A phase solubility study showed increased CIP-Ad solubility with CD concentration, pointing out complex formation. The evaluation of the antibacterial activity of CIP-Ad and the 2,3-O-dimethyl-β-CD/CIP-Ad or 2,3,6-O-trimethyl-β-CD/CIP-Ad complexes was performed on Staphylococcus epidermidis (S. epidermidis) strains. The Minimum Inhibitory Concentration (MIC) studies showed that the complex of CIP-Ad and 2,3-O-dimethyl-β-CD exhibited a similar antimicrobial activity to CIP-Ad alone, while the interaction with 2,3,6-O-trimethyl-β-CD increased MIC values. Antimicrobial assays on S. epidermidis biofilms demonstrated that the synergistic effect observed with the DspB/CIP association was partly maintained with the 2,3-O-dimethyl-β-CDs/CIP-Ad complex. To obtain this "all-in-one" drug delivery system, able to destroy the biofilm matrix and release the antibiotic simultaneously, we covalently grafted DspB on three carboxylic permethylated CD derivatives with different-length spacer arms. The strategy was validated by demonstrating that a DspB-permethylated-β-CD/ciprofloxacin-Ad system exhibited efficient antibiofilm activity.

Keywords: Dispersin B; antibiofilm; ciprofloxacin; cyclodextrin; inclusion complex.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Ciprofloxacin / chemistry
Ciprofloxacin / pharmacology
Cyclodextrins* / chemistry
Staphylococcus epidermidis
Thermodynamics

Substances

Cyclodextrins
Ciprofloxacin
Anti-Bacterial Agents

Grants and funding

RGP2/358/44./The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/358/44.