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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI117210-02
Application #
9188067
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Xu, Zuoyu
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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