Metal binding and structure-activity relationship of the metalloantibiotic peptide bacitracin

Bacitracin is a widely used metallopeptide Antibiotic produced by Bacillus subtilis and Bacillus licheniformis with a potent bactericidal activity directed primarily against Gram-positive organisms. This Antibiotic requires a divalent metal ion such as Zn(2+) for its biological activity, and has been reported to bind several Other transition metal ions, including Mn(2+), Co(2+), Ni(2+), and Cu(2+). Despite the widespread use of bacitracin since its discovery in the early 1940s, the structure-activity relationship of this drug has not been established and the coordination chemistry of its metal complexes was not fully determined until recently. This Antibiotic has been suggested to influence cell functioning through more than one route. Since Bacterial resistance against bacitracin is still rare despite several decades of widespread use, this Antibiotic can serve as an ideal lead for the design of potent peptidyl Antibiotics lacking Bacterial resistance. In this review, the results of physical (including NMR, EPR, and EXAFS) and molecular biological studies regarding the synthesis and structure of bacitracin, the coordination chemistry of its metal derivatives, the mechanism of its Antibiotic actions, its influence on membrane function, and its structure and function relationship are discussed.