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 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.