Faculty Opinions recommendation of Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase.

2017 ◽  
Author(s):  
Mark Dillingham
Keyword(s):  
Rna Polymerase ◽  
Nucleoside Analog ◽  
Bacterial Rna

scholarly journals Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase: pseudouridimycin

2017 ◽  
Author(s):  
Sonia I. Maffioli ◽  
Yu Zhang ◽  
David Degen ◽  
Thomas Carzaniga ◽  
Giancarlo Del Gatto ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Drug Development ◽  
Rna Polymerase ◽  
Binding Site ◽  
Bacterial Pathogens ◽  
Nucleoside Analog ◽  
Cross Resistance ◽  
Nucleoside Triphosphate ◽  
Antibacterial Drug ◽  
Bacterial Rna

There is an urgent need for new antibacterial drugs effective against bacterial pathogens resistant to current drugs1–2. Nucleoside-analog inhibitors (NAIs) of viral nucleotide polymerases have had transformative impact in treatment of HIV3and HCV4. NAIs of bacterial RNA polymerase (RNAP) potentially could have major impact on treatment of bacterial infection, particularly because functional constraints on substitution of RNAP nucleoside triphosphate (NTP) binding sites4-5could limit resistance emergence4-5. Here we report the discovery, from microbial extract screening, of an NAI that inhibits bacterial RNAP and exhibits antibacterial activity against a broad spectrum of drug-sensitive and drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a novel microbial natural product consisting of a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, potently and selectively inhibits bacterial growth in culture, and potently clears infection in a mouse model ofStreptococcus pyogenesperitonitis. PUM inhibits RNAP through a binding site on RNAP (the "i+1" NTP binding site) and mechanism (competition with UTP for occupancy of the "i+1" NTP binding site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. The results provide the first example of a selective NAI of bacterial RNAP, provide an advanced lead compound for antibacterial drug development, and provide structural information and synthetic routes that enable lead optimization for antibacterial drug development.

scholarly journals Discovery, properties, and biosynthesis of pseudouridimycin, an antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase

2018 ◽  
Vol 46 (3-4) ◽  
pp. 335-343 ◽  
Author(s):  
Sonia I. Maffioli ◽  
Margherita Sosio ◽  
Richard H. Ebright ◽  
Stefano Donadio
Keyword(s):  
Rna Polymerase ◽  
Nucleoside Analog ◽  
Bacterial Rna

scholarly journals Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase

Cell ◽  
2017 ◽  
Vol 169 (7) ◽  
pp. 1240-1248.e23 ◽  
Author(s):  
Sonia I. Maffioli ◽  
Yu Zhang ◽  
David Degen ◽  
Thomas Carzaniga ◽  
Giancarlo Del Gatto ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Nucleoside Analog ◽  
Bacterial Rna
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