1. Mefloquine synergism with anti-tuberculosis drugs and correlation to membrane effects: Biologic, spectroscopic and molecular dynamics simulations studies
- Author
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Emerson Teixeira da Silva, Nichole Osti Silva, Maria C.S. Lourenço, Raoni Schroeder B. Gonçalves, Carla Roberta Lopes de Azambuja Borges, Marcus V. N. de Souza, João Luis Rheingantz Scaini, Pedro Eduardo Almeida da Silva, Marinalva Cardoso dos Santos, Adriano Velasque Werhli, Beatriz Gonçalves Rodrigues, Márcio Vinicius Costa Lopes, Karina S. Machado, Sandra Cruz dos Santos, and Vânia Rodrigues de Lima
- Subjects
Magnetic Resonance Spectroscopy ,Membrane permeability ,Antitubercular Agents ,Microbial Sensitivity Tests ,Molecular Dynamics Simulation ,01 natural sciences ,Biochemistry ,Mycobacterium tuberculosis ,Structure-Activity Relationship ,Glycolipid ,Spectroscopy, Fourier Transform Infrared ,Drug Discovery ,medicine ,Molecular Biology ,Liposome ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Isoniazid ,Phosphorus Isotopes ,Pyrazinamide ,biology.organism_classification ,0104 chemical sciences ,Mefloquine ,010404 medicinal & biomolecular chemistry ,Membrane ,Permeability (electromagnetism) ,Biophysics ,medicine.drug - Abstract
Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.
- Published
- 2021