Role of internal loop dynamics in antibiotic permeability of outer membrane porins

Author:

Vasan Archit Kumar123ORCID,Haloi Nandan123ORCID,Ulrich Rebecca Joy456ORCID,Metcalf Mary Elizabeth7,Wen Po-Chao13ORCID,Metcalf William W.7ORCID,Hergenrother Paul J.456,Shukla Diwakar689,Tajkhorshid Emad1234ORCID

Affiliation:

1. NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

2. Center for Biophysics and Quantitative Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

3. Department of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801

4. Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801

5. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

6. Cancer Center at Illinois, University of Illinois at Urbana–Champaign, Urbana, IL 61801

7. Department of Microbiology, University of Illinois at Urbana–Champaign, Urbana, IL 61801

8. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana–Champaign, Urbana, IL 61801

9. National Center for Supercomputing Applications, University of Illinois at Urbana–Champaign, Urbana, IL 61801

Abstract

Significance Antibiotic resistance in Gram-negative pathogens has been identified as an urgent threat to human health by the World Health Organization. The major challenge with treating infections by these pathogens is developing antibiotics that can traverse the dense bacterial outer membrane (OM) formed by a mesh of lipopolysaccharides. Effective antibiotics permeate through OM porins, which have evolved for nutrient diffusion; however, the conformational states of these porins regulating permeation are still unclear. Here, we used molecular dynamics simulations, free energy calculations, Markov-state modeling, and whole-cell accumulation assays to provide mechanistic insight on how a porin shifts between open and closed states. We provide a mechanism of how Gram-negative bacteria confer resistance to antibiotics.

Funder

HHS | National Institutes of Health

National Science Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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