Microcin C7 (McC) is a potent natural product antimicrobial produced by enterobacteria. McC enters the target cell using a Trojan horse strategy, in which the active portion of the antibiotic is coupled to a peptide carrier that faciliates import into target cell through active transporters. We have characterized several biosynthetic clusters for that produce the same antibiotic component but with different peptide attachments. Presumably, changes in the peptide allow for import through different transport systems that are specific to different bacterial species. Here we seek to: i. install variations in the peptide carrer allowing the molecule to be taken up by diverse bacteria. ii. re-design the peptide carrier so that it can be more effectively imported into susceptible organisms.
This research plan focuses on the in vivo and in vitro characterization of the mechanisms by which the aspartyl-tRNA synthetase inhibitor, microcin C7, is synthesized and on using this knowledge to produce more potent molecules with broader spectrum activities. Knowledge gained from this proposal will further benefit the development of this powerful class of antibiotics.
| Tsibulskaya, Darya; Mokina, Olga; Kulikovsky, Alexey et al. (2017) The Product of Yersinia pseudotuberculosis mcc Operon Is a Peptide-Cytidine Antibiotic Activated Inside Producing Cells by the TldD/E Protease. J Am Chem Soc 139:16178-16187 |
| Metelev, Mikhail; Osterman, Ilya A; Ghilarov, Dmitry et al. (2017) Klebsazolicin inhibits 70S ribosome by obstructing the peptide exit tunnel. Nat Chem Biol 13:1129-1136 |
| Serebryakova, Marina; Tsibulskaya, Darya; Mokina, Olga et al. (2016) A Trojan-Horse Peptide-Carboxymethyl-Cytidine Antibiotic from Bacillus amyloliquefaciens. J Am Chem Soc 138:15690-15698 |
