Passive Diffusion of Ciprofloxacin and its Metalloantibiotic: A Computational and Experimental study |
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| Affiliation: | 1. LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal;2. LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal;1. Graduate School of Science, Nagoya University, Nagoya, Aichi 464-8602, Japan;2. Graduate School of Informatics, Nagoya University, Nagoya, Aichi 464-8601, Japan;3. Graduate School of Science, Osaka City University, Osaka, Osaka 558-8585, Japan;4. The OCU Advanced Research Institute for Natural Science and Technology (OCARINA), Osaka City University, Osaka, Osaka 558-8585, Japan;1. Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea;2. Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;1. Department of Biomolecular Sciences, Weizmann Institute of Science, Israel;2. Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany;3. Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany;4. Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Im Neuenheimer Feld 205, Heidelberg, Germany;1. LEPABE – Dep. of Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal;2. ESEI – Dep. of Computer Science, University of Vigo, Edificio Politécnico, Campus Universitario As Lagoas S/n, 32004, Ourense, Spain;3. CINBIO - Centro de Investigaciones Biomédicas, University of Vigo, Campus Universitario Lagoas-Marcosende, 36310, Vigo, Spain;4. SING Research Group, Galicia Sur Health Research Institute (ISS Galicia Sur), SERGAS-UVIGO, 36312, Vigo, Spain;5. CEB - Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal |
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| 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. |
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| Keywords: | fluoroquinolones copper complexes membrane permeation molecular dynamics spectroscopy FQ" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" fluoroquinolones Cpx" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" ciprofloxacin CuCpxPhen" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" Ternary complex of copper, ciprofloxacin and phenanthroline COM" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" centre of mass PG" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" phosphatidylglycerol CL" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" cardiolipin PE" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" phosphatidylethanolaminee PC" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" phosphatidylethanolamine Phen" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" 1,10-phenathroline CuFQPhen" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" Ternary complex of copper, fluoroquinolone and phenanthroline Partition constant MD" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" Molecular dynamics PTS" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" 1,3,6,8-pyrenetetrasulfonic acid tetrasodium salt ST" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" steady-state TR" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" time-resolved POPG" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) POPC" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine LUV" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" large unilamellar vesicles MLV" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" multilamellar vesicles RESP" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" restricted electrostatic potential US" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" umbrella sampling SD" },{" #name" :" keyword" ," $" :{" id" :" k0245" }," $$" :[{" #name" :" text" ," _" :" standard deviation |
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