Summary information and primary citation
- PDB-id
-
5x21;
DSSR-derived features in text and
JSON formats
- Class
- transferase-DNA
- Method
- X-ray (3.323 Å)
- Summary
- Crystal structure of thermus thermophilus transcription
initiation complex with gpa and pseudouridimycin (pum)
- Reference
-
Maffioli SI, Zhang Y, Degen D, Carzaniga T, Del Gatto G,
Serina S, Monciardini P, Mazzetti C, Guglierame P,
Candiani G, Chiriac AI, Facchetti G, Kaltofen P, Sahl HG,
Deho G, Donadio S, Ebright RH (2017): "Antibacterial
Nucleoside-Analog Inhibitor of Bacterial RNA
Polymerase." Cell, 169,
1240-1248.e23. 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.
