Molecular Interactions of Cephalosporins with the Deep Binding Pocket of the RND Transporter AcrB

The
drug/proton antiporter AcrB, part of the major efflux pump
AcrABZ-TolC in Escherichia coli, is
characterized by its impressive ability to transport chemically diverse
compounds, conferring a multidrug resistance phenotype. However, the
molecular features differentiating between good and poor substrates
of the pump have yet to be identified. In this work, we combined molecular
docking with molecular dynamics simulations to study the interactions
between AcrB and two representative cephalosporins, cefepime and ceftazidime
(a good and poor substrate of AcrB, respectively). Our analysis revealed
different binding preferences of the two compounds toward the subsites
of the large deep binding pocket of AcrB. Cefepime, although less
hydrophobic than ceftazidime, showed a higher affinity than ceftazidime
for the so-called hydrophobic trap, a region known for binding inhibitors
and substrates. This supports the hypothesis that surface complementarity
between the molecule and AcrB, more than the intrinsic hydrophobicity
of the antibiotic, is a feature required for the interaction within
this region. Oppositely, the preference of ceftazidime for binding
outside the hydrophobic trap might not be optimal for triggering allosteric
conformational changes needed to the transporter to accomplish its
function. Altogether, our findings could provide valuable information
for the design of new antibiotics less susceptible to the efflux mechanism.