Interaction of Cephalosporins with Human Serum Albumin: A Structural Study

Modification of the R1 and R2 side chain structures has
been used
as the main strategy to expand the spectrum of cephalosporins and
impart resistance to hydrolysis by β-lactamases. These structural
modifications also result in a wide range of plasma protein binding,
especially with human serum albumin (HSA). Here, we determined the
crystal structures of the HSA complexes with two clinically important
cephalosporins, ceftriaxone and cefazolin, and evaluated the binding
of cephalosporin to HSA by susceptibility testing and competitive
binding assay. Ceftriaxone and cefazolin bind to subdomain IB of HSA,
and their cephem core structures are recognized by Arg117 of HSA.
Tyr161 of HSA changes its rotamer depending on the cephalosporin,
resulting in alterations of the cavity shape occupied by the R2 side
chain of cephalosporins. These findings provide structural insight
into the mechanisms underlying the HSA binding of cephalosporins.