Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 433, Issue 9, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.166911
Keywords
fluoroquinolones; copper complexes; membrane permeation; molecular dynamics; spectroscopy
Categories
Funding
- Associate Laboratory for Green Chemistry Unit -LAQV [UID/QUI/50006/2019, UIDB/50006/2020]
- Applied Molecular Biosciences Unit -UCIBIO - FCT/MCTES [UID/Multi/04378/2019]
- Medical Biochemistry and Biophysics Doctoral Programme (M2B-PhD)
- FCT, Portugal [PD/BD/114178/2016]
- FCT
- REQUIMTE-LAQV [REQUIMTE 2019-34]
- scientific employment stimulus -individual call of 2018 [CEECIND/01374/2018]
- Fundação para a Ciência e a Tecnologia [PD/BD/114178/2016] Funding Source: FCT
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The study indicates that the ternary copper complex CuCpxPhen exhibits higher membrane permeabilization activity, larger partition, and a more favorable free energy landscape for permeation compared to ciprofloxacin across lipid bilayers, especially showing enhanced specificity towards anionic membranes.
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. (C) 2021 Elsevier Ltd. All rights reserved.
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