Simulated Drug Efflux for the AbgT Family of Membrane Transporters

Drug extrusion through molecular efflux pumps is an important mechanism for the survival of many pathogenic bacteria by removing drugs, providing multidrug resistance (MDR). Understanding molecular mechanisms for drug extrusion in multidrug efflux pumps is important for the development of new antire...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2021-11, Vol.61 (11), p.5673-5681
Main Authors: Shome, Sayane, Sankar, Kannan, Jernigan, Robert L.
Format: Article
Language:English
Subjects:
Antibiotics
Bacteria
Benzoic acid
Biosynthesis
Drug resistance
Drugs
Efflux
Extrusion
Folic acid
Ligands
Molecular dynamics
Pharmaceutical Modeling
Pumps
Residues
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Summary:Drug extrusion through molecular efflux pumps is an important mechanism for the survival of many pathogenic bacteria by removing drugs, providing multidrug resistance (MDR). Understanding molecular mechanisms for drug extrusion in multidrug efflux pumps is important for the development of new antiresistance drugs. The AbgT family of transporters involved in the folic acid biosynthesis pathway represents one such important efflux pump system. In addition to the transport of the folic acid precursor p-amino benzoic acid (PABA), members of this family are involved in the efflux of several sulfa drugs, conferring drug resistance to the bacteria. With the availability of structures for two members of this family (YdaH and MtrF), we investigate molecular pathways for transport of PABA and a sulfa drug (sulfamethazine) particularly for the YdaH transporter using steered molecular dynamics. Our analyses reveal the probable ligand migration pathways through the transporter, which also identifies key residues along the transport pathway. In addition, simulations using both PABA and sulfamethazine show how the protein is able to transport ligands of different shapes and sizes out of the pathogen. Our observations confirm previously reported functional residues for transport along the pathways by which YdaH transporters achieve antibiotic resistance to shuttle drugs out of the cells.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.1c00516