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ACS Infect Dis. 2018 Jun 8;4(6):860-867. doi: 10.1021/acsinfecdis.8b00105. Epub 2018 May 7.

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

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Department of Chemistry & Biochemistry , University of Notre Dame , 352 McCourtney Hall , Notre Dame , Indiana 46556 , United States.
Department of Civil & Environmental Engineering & Earth Sciences , University of Notre Dame , 156 Fitzpatrick Hall , Notre Dame , Indiana 46556 , United States.
Department of Biological Sciences , University of Notre Dame , Notre Dame , Indiana 46556 , United States.


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.


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

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