THE LANTIBIOTIC MERSACIDIN INHIBITS PEPTIDOGLYCAN SYNTHESIS BY TARGETING LIPID-II

The lantibiotic mersacidin exerts its bactericidal action by inhibitio n of peptidoglycan biosynthesis. It interferes with the membrane-assoc iated transglycosylation reaction; during this step the ultimate monom eric peptidoglycan precursor, prenyl-pyrophosphoryl-MurNAc-(pentapepti de)-GlcNAc (lipid II) is converted into polymeric nascent peptidoglyca n. In the present study we demonstrate that the molecular basis of thi s inhibition is the interaction of mersacidin with lipid II. The adsor ption of [C-14]mersacidin to growing cells, as well as to isolated mem branes capable of in vitro peptidoglycan synthesis, was strictly depen dent on the availability of lipid II, and antibiotic inhibitors of lip id II formation strongly interfered with this binding. Direct evidence for the interaction was provided by studies with isolated lipid II. [ C-14]mersacidin associated tightly with [C-14]lipid II micelles; the c omplex was stable even in the presence of 1% sodium dodecyl sulfate. F urthermore, the addition of isolated lipid II to the culture broth eff iciently antagonized the bactericidal activity of mersacidin, In contr ast to the glycopeptide antibiotics, complex formation does not involv e the C-terminal D-alanyl-D-alanine moiety of the lipid intermediate. Thus. the interaction of mersacidin with lipid II apparently occurs vi a a binding site which is not targeted by any antibiotic currently in use.