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The RNA Polymerase Switch Region Is a Target for Inhibitors
Jayanta Mukhopadhyay1,2,4,6,Kalyan Das3,4,6,Sajida Ismail1,2,4,David Koppstein1,2,4,Minyoung Jang1,2,4,Brian Hudson3,4,Stefan Sarafianos3,4,Steven Tuske3,4,Jay Patel3,4,Rolf Jansen5,Herbert Irschik5,Eddy Arnold3,4,,andRichard H. Ebright1,2,4,,
1 Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ 08854, USA
2 Waksman Institute, Rutgers University, Piscataway, NJ 08854, USA
3 Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, USA
4 Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA
5 Helmholtz Centre for Infection Research, Inhoffenstrae 7, D-38124 Braunschweig, Germany
SUMMARY
The α-pyrone antibiotic myxopyronin (Myx) inhibits bacterial RNA polymerase (RNAP). Here, through a combination of genetic, biochemical, and structural approaches, we show that Myx interacts with the RNAP switch regionthe hinge that mediates opening and closing of the RNAP active center cleftto prevent interaction of RNAP with promoter DNA. We define the contacts between Myx and RNAP and the effects of Myx on RNAP conformation and propose that Myx functions by interfering with opening of the RNAP active-center cleft during transcription initiation. We further show that the structurally related α-pyrone antibiotic corallopyronin (Cor) and the structurally unrelated macrocyclic-lactone antibiotic ripostatin (Rip) function analogously to Myx. The RNAP switch region is distant from targets of previously characterized RNAP inhibitors, and, correspondingly, Myx, Cor, and Rip do not exhibit crossresistance with previously characterized RNAP inhibitors. The RNAP switch region is an attractive target for identification of new broad-spectrum antibacterial therapeutic agents.
