Structures of RNA polymerase-antibiotic complexes.
Inhibition of bacterial RNA polymerase (RNAP) is an established strategy for antituberculosis therapy and broad-spectrum antibacterial therapy. Crystal structures of RNAP-inhibitor complexes are available for four classes of antibiotics: rifamycins, sorangicin, streptolydigin, and myxopyronin. The structures define three different targets, and three different mechanisms, for inhibition of bacterial RNAP: (1) rifamycins and sorangicin bind near the RNAP active center and block extension of RNA products; (2) streptolydigin interacts with a target that overlaps the RNAP active center and inhibits conformational cycling of the RNAP active center; and (3) myxopyronin interacts with a target remote from the RNAP active center and functions by interfering with opening of the RNAP active-center cleft to permit entry and unwinding of DNA and/or by interfering with interactions between RNAP and the DNA template strand. The structures enable construction of homology models of pathogen RNAP-antibiotic complexes, enable in silico screening for new antibacterial agents, and enable rational design of improved antibacterial agents.
Ho
Mary X
MX
Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA.
Hudson
Brian P
BP
Das
Kalyan
K
Arnold
Eddy
E
Ebright
Richard H
RH
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
D000900:Anti-Bacterial Agents; D012321:DNA-Directed RNA Polymerases