Seventy-five years of research on protein binding - do we ever understand?

This review summarizes evidence that the impact of protein binding of the activity of antibiotics is multifaceted and more complex than indicated by the numerical value of protein binding alone. A plethora of studies has proven that protein binding of antibiotics matters, as the free fraction only is antibacterially active and governs pharmacokinetics. Several studies have indicated that independent from protein binding of immunoglobulin G, albumin, alpha(1)-acid-glycoprotein, and pulmonary surfactant acted synergistically with antibacterial agents, thus suggesting that some intrinsic properties of serum proteins may have mediated serum-antibiotic synergisms. It has been demonstrated that IgG and albumin permeabilized Gramnegative and Gram-positive bacteria and facilitated the uptake of poorly penetrating antibiotics. Alpha-alpha(1)-acid-glycoprotein and pulmonary surfactant also exerted a permeabilizing activity, but proof that this property results in a sensitizing effect is missing. The permeabilizing effect of serum proteins may explain why serum-antibiotic synergisms do not represent a general phenomenon but are limited to specific drug-bug associations only. Although evidence has been generated to support the hypothesis that native serum proteins interact synergistically with antibiotics, systematic and well-controlled studies have to be performed to substantiate this phenomenon. The interactions between serum proteins and bacterial surfaces are driven by physicochemical forces. However, preparative techniques, storage conditions, and incubation methods have a significant impact on the intrinsic activities of these serum proteins affecting serum-antibiotic synergisms, so these techniques have to be standardized; otherwise, contradictory data or even artifacts will be generated.