2. Academic Validation
  3. Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase

Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase

  • Cell. 2017 Jun 15;169(7):1240-1248.e23. doi: 10.1016/j.cell.2017.05.042.
Sonia I Maffioli 1,  Yu Zhang 2,  David Degen 2,  Thomas Carzaniga 3,  Giancarlo Del Gatto 4,  Stefania Serina 1,  Paolo Monciardini 1,  Carlo Mazzetti 4,  Paola Guglierame 5,  Gianpaolo Candiani 6,  Alina Iulia Chiriac 7,  Giuseppe Facchetti 6,  Petra Kaltofen 6,  Hans-Georg Sahl 7,  Gianni Dehò 3,  Stefano Donadio 8,  Richard H Ebright 9
Affiliations

Affiliations

  • 1 NAICONS Srl, 20139 Milan, Italy; Vicuron Pharmaceuticals, 21040 Gerenzano, Italy.
  • 2 Waksman Institute and Department of Chemistry, Rutgers University, Piscataway, NJ 08854, USA.
  • 3 Department of Bioscience, University of Milan, 20122 Milan, Italy.
  • 4 NAICONS Srl, 20139 Milan, Italy.
  • 5 NeED Pharma Srl, 20139 Milan, Italy.
  • 6 Vicuron Pharmaceuticals, 21040 Gerenzano, Italy.
  • 7 Institute of Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53012 Bonn, Germany.
  • 8 NAICONS Srl, 20139 Milan, Italy; Vicuron Pharmaceuticals, 21040 Gerenzano, Italy. Electronic address: sdonadio@naicons.com.
  • 9 Waksman Institute and Department of Chemistry, Rutgers University, Piscataway, NJ 08854, USA. Electronic address: ebright@waksman.rutgers.edu.
PMID: 28622509 DOI: 10.1016/j.cell.2017.05.042
Abstract

Drug-resistant Bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits Bacterial RNA polymerase (RNAP) and exhibits Antibacterial activity against drug-resistant Bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N-hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits Bacterial RNAP in vitro, inhibits Bacterial growth in culture, and clears Infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition 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. PUM is a highly promising lead for Antibacterial therapy.

Keywords

Pseudouridimycin (PUM); RNA polymerase; RNA polymerase inhibitor; antibacterial; antibiotic; antimicrobial resistance; microbial extract screening; nucleoside-analog inhibitor; transcription; transcription inhibitor.

Figures
Products