Passive Diffusion of Ciprofloxacin and its Metalloantibiotic: A Computational and Experimental study. Issue 9 (30th April 2021)

• Record Type: Journal Article
• Authors: Sousa, Carla F.; Coimbra, João T.S.; Ferreira, Mariana; Pereira-Leite, Catarina; Reis, Salette; Ramos, Maria J.; Fernandes, Pedro A.; Gameiro, Paula
• Is Part Of: Journal of molecular biology. Volume 433:Issue 9(2021)
• Publication Date: 2021-04-30
• Subjects: fluoroquinolones -- copper complexes -- membrane permeation -- molecular dynamics -- spectroscopy; FQ fluoroquinolones -- Cpx ciprofloxacin -- CuCpxPhen Ternary complex of copper, ciprofloxacin and phenanthroline -- COM centre of mass -- PG phosphatidylglycerol -- CL cardiolipin -- PE phosphatidylethanolaminee -- PC phosphatidylethanolamine -- Phen 1, 10-phenathroline -- CuFQPhen Ternary complex of copper, fluoroquinolone and phenanthroline -- Kp Partition constant -- MD Molecular dynamics -- PTS 1, 3, 6, 8-pyrenetetrasulfonic acid tetrasodium salt -- ST steady-state -- TR time-resolved -- POPG 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) -- POPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine -- LUV large unilamellar vesicles -- MLV multilamellar vesicles -- RESP restricted electrostatic potential -- US umbrella sampling -- SD standard deviation; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.166911
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Comparison of the translocation of ciprofloxacin and its metalloantibiotic across the membrane. The net charge of the lipid bilayer influences the molecule's affinity and permeation. The metalloantibiotic shows a larger affinity for the membrane. The metalloantibiotic shows a more favourable free energy profile for permeation across the anionic membrane. The metalloantibiotic shows potential to be used as an alternative to FQ against resistant infections. Abstract: Fluoroquinolones (FQ) are antibiotics widely used in clinical practise, but the development of bacterial resistance to these drugs is currently a critical public health problem. In this context, ternary copper complexes of FQ (CuFQPhen) have been studied as a potential alternative. In this study, we compared the passive diffusion across the lipid bilayer of one of the most used FQ, ciprofloxacin (Cpx), and its ternary copper complex, CuCpxPhen, that has shown previous promising results regarding antibacterial activity and membrane partition. A combination of spectroscopic studies and molecular dynamics simulations were used and two different model membranes tested: one composed of anionic phospholipids, and the other composed of zwitterionic phospholipids. The obtained results showed a significantly higher membrane permeabilization activity, larger partition, and a more favourable free energy landscape for the permeation of CuCpxPhen across the membrane, when compared to Cpx. Furthermore, the computational results indicated a more favourable translocation of CuCpxPhen across the anionic membrane, when compared to the zwitterionic one, suggesting a higher specificity towards the former. These findings are important to decipher the influx mechanism of CuFQPhen in bacterial cells, which is crucial for the ultimate use of CuFQPhen complexes as an alternative to FQ to tackle multidrug-resistant bacteria.