Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics

Shusuke Tomoshige, David A. Dik, Masaaki Akabane-Nakata, Chinedu S. Madukoma, Jed F. Fisher, Joshua D. Shrout, Shahriar Mobashery

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a cobiosynthesized β-lactam antibiotic. β-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and penicillin-binding protein (by β-lactams) activities results in deformation of the septal cell wall, observed microscopically as a bulge preceding bacterial cell lysis. We describe a practical synthesis of the three naturally occurring bulgecin iminosaccharides and their mechanistic evaluation in a series of microbiological studies. These studies identify potentiation by the bulgecin at subminimum inhibitory concentrations of the β-lactam against three pathogenic Gram-negative bacteria and establish for the first time that this potentiation results in a significant increase in the bactericidal efficacy of a clinical β-lactam.

Original languageEnglish
Pages (from-to)860-867
Number of pages8
JournalACS Infectious Diseases
Volume4
Issue number6
DOIs
Publication statusPublished - 2018 Jun 8
Externally publishedYes

Keywords

  • antibiotic resistance
  • bacteria
  • cell wall
  • lytic transglycosylases
  • β-lactam antibiotics

ASJC Scopus subject areas

  • Infectious Diseases

Fingerprint Dive into the research topics of 'Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics'. Together they form a unique fingerprint.

  • Cite this

    Tomoshige, S., Dik, D. A., Akabane-Nakata, M., Madukoma, C. S., Fisher, J. F., Shrout, J. D., & Mobashery, S. (2018). Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the β-Lactam Antibiotics. ACS Infectious Diseases, 4(6), 860-867. https://doi.org/10.1021/acsinfecdis.8b00105