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Permeability Through Bacterial Porins Dictates Whole Cell Compound Accumulation

preprint
submitted on 20.02.2020 and posted on 21.02.2020 by Silvia Acosta Gutiérrez, Igor Bodrenko, Matteo Ceccarelli
The lack of new drugs for Gram-negative pathogens is a global threat to modern medicine. The complexity of their cell envelope, with an additional outer membrane, hinders internal accumulation and thus, the access of molecules to targets. Our limited understanding of the molecular basis for compound influx and efflux from these pathogens is a major bottleneck for the discovery of effective antibacterial compounds. Here we analyse the correlation between the whole-cell compound accumulation of ~200 molecules and their predicted porin permeability coefficient (influx), using a recently developed scoring function. We found a strong linear relationship (75%) between the two, confirming porins key role in compound penetration. Further, the remarkable prediction ability of the scoring function demonstrates its potentiality to guide the optimization of hits to leads as well as the possibility of screening ultra-large virtual libraries. Eventually, the analysis of false positives, molecules with high-predicted influx but low accumulation, provides new hints on the molecular properties behind efflux.

Funding

Translocation consortia, Innovative Medicines Initiatives Joint Undertaking under Grant Agreement no. 115525 (FP7) and EFPIA companies in kind contribution

MIUR PRIN project 2015795S5W_005

History

Email Address of Submitting Author

silvia.gutierrez@ucl.ac.uk

Institution

University College London

Country

United Kingdom

ORCID For Submitting Author

0000-0002-0122-9769

Declaration of Conflict of Interest

None

Exports