Structural Analysis and Protein Binding of Cephalosporins

Abstract

Cephalosporins are a widely used subclass of β-lactam antibiotics that demonstrate variable protein binding independent of generation or antibiotic coverage. Prior work analyzed carbon 3 (C3) and carbon 7 (C7) substituents (locations of R2 and R1 groups respectively) for protein binding interactions. This study builds upon these results with statistical analysis of additional agents of the class. Chemical structures of 23 cephalosporins were used to identify the presence of 40 functional groups, and correlative relationships were identified using established protein binding data. Four functional groups were significantly correlated with protein binding: tetrazole (positive association), pyridinium, primary amine, and quaternary amine (negative associations). Cephalosporins with a negative charge at physiological pH were associated with increased protein binding. Analysis of tetrazole-containing cephalosporins and ceftriaxone indicates the need for further study of the potential role in protein binding of neutral or negatively charged aromatic nitrogen heterocycles linked at the C3 position by a thiomethylene group.

Interaction of Cephalosporins with Human Serum Albumin: A Structural Study

“…Kanis and colleagues performed statistical analysis between the structural characteristics of cephalosporins and their plasma protein bindings and reported that a net negative charge and the thiomethylenelinked aromatic nitrogen heterocyclic ring at the R2 side chain of cephalosporins are associated with increased plasma protein binding. 3 These observations are consistent with our results and can be explained by the structures that we determined. The crystal structures of the HSA in complex with ceftriaxone or cefazolin revealed that the substrate binding site at subdomain IB of HSA is a positively charged environment, making it more favorable for the binding of anionic compounds (Figure 6a).…”

“…On the other hand, the R1 side chains of cephalosporins lack distinct structural features relating to plasma protein binding, and bulky or branched side chains do not appear to impact plasma protein binding (Figure 2). 3 These observations suggest that the R1 chamber is tolerant, and the cephalosporin molecules access the entrance of the R1 chamber and reach the chambers of the cephem core and R2.…”

“…5 Thus, the need to optimize ceftriaxone dosing based on albumin concentration in addition to the underlying condition of the patient has been proposed. 5,6 On the other hand, ceftazidime displays minimal plasma protein binding 3,7 (Figure 2), and its recommended dose and route of administration are optimized mainly based on the renal function, such as the creatinine clearance rate. 8,9 HSA plays a biological role in maintaining the oncotic pressure in the bloodstream since it constitutes approximately 60% of the total plasma protein at a concentration of ≈600 μM.…”

Systematic Review and Meta-Analysis of the Effect of Loop Diuretics on Antibiotic Pharmacokinetics

“…The observed increase in AUC is less likely explained by electrostatic interactions leading to greater passive reabsorption. Cephalosporins are generally known to be negatively or neutrally charged at physiologic pH [ 47 ], whereas aminoglycosides may be neutrally or positively charged [ 48 , 49 ]. However, increased AUC was observed for all antibiotics regardless of class.…”

Colorimetric detection of norfloxacin and ceftazidime by modified materials

“…By increasing the solution pH, ceftazidime exists as either neutral zwitterions (pH 2. 77 -4.26) or negatively charged species (pH > 4.26) [103]. In this work, PEI-sponges were used to extract ceftazidime through the electrostatic interaction between the negatively charged ceftazidime and the positively charged PEI.…”