Synthesis and antimicrobial evaluation of new cephalosporin derivatives containing cyclic disulfide moieties

Abstract

Due to a steady increase of microbial resistance, there is a need to increase the effectiveness of antibiotic performance by involving additional mechanisms of their penetration or retention for their better action. Cephalosporins are a successful group of antibiotics to combat pathogenic microorganisms, including drug-resistant strains. In this study, we investigated the effect of newly synthesized cephalosporin derivatives with cyclic disulfide modifications against several Gram-positive and Gram-negative strains as well as against biofilm formation. The incorporation of asparagusic acid was found to be effective in improving the activity of the drug against Gramnegative strains. Furthermore, we could demonstrate the successful inhibition of biofilm formation for S. aureus and P. aeruginosa at similar concentrations as obtained against planktonic cells. We propose that the incorporation of cyclic disulfides is one additional strategy to improve antibiotic activity and to combat bacterial infections.

Antibody-drug conjugates to treat bacterial biofilms

“…[28][29][30]34 For bacteria, such reports are scant and in fact antibiotics acting in the cytoplasm were inactivated via their conversion to disulfide-containing derivatives, possibly suggesting conjugation to the bacterial cell surface and thereby arrested drug cell entry. 31 In recent studies, Shchelik and Gademann 51,52 observed that the disulfide containing derivatives of vancomycin and cephalosporin were superior to the parent antibiotic molecules, although no mechanism for the involvement of the disulfide functionality was provided to explain the enhanced drug efficacy of the newly synthesized compounds. In our hands, attempts to block the bacterial cell surface thiols with maleimide-based sulfhydryl poisons 30 were met with limited success (data not shown).…”