Elucidating The Mechanism of Action of the S-linked Glycopeptide Sublancin 168

Infectious diseases are a continuous threat to human health, and the rapid development of resistance against antibiotics among bacteria not only decreases the effectiveness of known antibiotics but also increases the need for the discovery of novel drugs. Sublancin 168, produced by Bacillus subtilis 168, contains a glucose moiety linked to a cysteine residue and therefore contains an unprecedented post-translational modification. In addition, sublancin 168 has been shown to be extremely stable; its antimicrobial activity is primarily against Bacillus species, and unlike many known antibiotics, it does not inhibit lipid II polymerization. Its extreme stability and unique structure have led us to hypothesize that sublancin has a novel antimicrobial mechanism of action. We have employed the use of various biochemical, microbiological, and genomic tools to characterize sublancin’s activity.  Data obtained from comparative genomic analysis and global gene expression (DNA microarrays) has identified the PTS-glucose specific transport system as a possible mechanism by which sublancin enters the cell. Future efforts include investigating sublancin’s localization in the cell by creating fluorescent sublancin analogs. A clear understanding of how this unique antibiotic exerts its antimicrobial activity may facilitate the development of new antibiotics with novel modes of action that can evade known resistance pathways. Ultimately we will attempt to shed light on exploitable pathways to better understand, target, and treat bacterial infections.