Biophysical Society Thematic Meeting | Stockholm 2022

Physical and Quantitative Approaches to Overcome Antibiotic Resistance

Poster Abstracts

27-POS Board 27 MODELLING THE EFFECT OF HYDROPHOBICITY ON ANTIBIOTIC PASSIVE PERMEATION AND ITS IMPACT ON BACTERIAL BIOAVAILABILITY Carla F. Sousa 1 ; Mohamed A. M. Kamal 1,2 ; Robert Richter 1 ; Olga V. Kalinina 1,3 ; Claus-Michael Lehr 1,2 ; 1 Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany Antibiotic bioavailability in the bacterial cell is crucial for drug efficiency. Specifically, permeation by passive diffusion may be highly relevant, since facilitated routes of influx (i.e. protein channels or transporters) are frequently hindered in resistant bacteria. Here, we use molecular dynamics simulations to investigate the impact of changes in hydrophobicity on the permeability of a series of Pseudomonas quorum sensing inhibitors across membrane models. This set of drugs have a common 2-nitrophenyl scaffold, connected to an alcohol with an alkyl chain of increasing length, corresponding to increasing hydrophobicity. 1 We have determined a direct correlation between hydrophobicity and permeability, using the inhomogeneous solubility diffusion model. This correlation does not fit, however, the experimental results, indicating an overestimation of the permeability of the most hydrophobic compounds. On the other hand, an analysis of the diff erence between ΔG max and ΔG min led to a permeability ranking that better agrees with experimental results, pointing to similar permeabilities for this set of molecules. Additionally, we showed that drug orientation across the bilayer has impact on the permeation process, as solutes that do not tend to flip at the membrane center permeate more favorably.Hence, using in silico methods, we were able to assess the impact of hydrophobicity on drug’s passive diffusion and provide additional atomistic detailed information on the permeation process. Overall, our results indicate that hydrophobicity should not play a crucial role for the passive permeation of this set of drugs. This study evidences the potential of combining computational and experimental data to study drug permeability and contribute to the development of more effective drugs.1. Storz, M. P.; Allegretta, G.; Kirsch, B.; Empting, M.; Hartmann, R. W., From in vitro to in cellulo: structure–activity relationship of (2 nitrophenyl)methanol derivatives as inhibitors of PqsD in Pseudomonas aeruginosa. Organic & Biomolecular Chemistry 2014, 12 (32), 6094-6104. 2 Saarland University, Department of Pharmacy, Saarbrucken, Germany 3 Saarland University, Faculty of Medicine, Saarbrucken, Germany

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