Modified tunicamycins, streptovirudins and quinovosamycins: potent enhancers of the penicillin antibiotics

S1.4 Glycans at the host-pathogen interface
Location (hall): 
Start/end time: 
Monday, July 1, 2019 - 12:00 to 12:15

Neil Price1, Michael Jackson1, Todd Naumann1, John Bannantine1, Jenny Hering2, Gisela  Branden3, Margareta Ek2, Vinayak Singh5, Valerie Mizrahi5, Katarina Mikusova4

1U.S. Department of Agriculture, Peoria, United States, 2AstraZeneca Ltd., Gothenburg, Sweden, 3University of Gothenburg, Gothenburg, Sweden, 4Comenius University, Bratislava, Slovakia, 5University of Cape Town, Cape Town, South Africa

Tunicamycin is lethal to bacteria and eukaryotes either by blocking cell wall biosynthesis or protein N-glycosylation, respectively. The tunicamycin uracil group mimics the UDP-HexNAc donor substrate, binding to a uridyl binding pocket within PNPT translocase enzymes. This is stabilized by a noncovalent π–πstacking interaction with a conserved Phe within the PNPT active site.  We have structurally modified tunicamycins (TunR1 and TunR2) to be less toxic to animal cells, but which retain the antibacterial activity. TunR1 and TunR2 are also potent enhancers of the β-lactam family of antibiotics, resulting in increased activity of penicillins, cephems, and carbapenems. TunR2 in which the uridyl group is converted to a 5,6-dihydrouridyl has low eukaryotic toxicity, and enhanced aminothiazolidyl cephalosporins by >128-fold against B. subtilis and several pathogenic mycobacterial strains.