New target for inhibition of bacterial RNA polymerase: ‘switch region’

Abstract

A new drug target-- the "switch region"--has been identified within bacterial RNA polymerase (RNAP), the enzyme that mediates bacterial RNA synthesis. The new target serves as the binding site for compounds that inhibit bacterial RNA synthesis and kill bacteria. Since the new target is present in most bacterial species, compounds that bind to the new target are active against a broad spectrum of bacterial species. Since the new target is different from targets of other antibacterial agents, compounds that bind to the new target are not cross-resistant with other antibacterial agents. Four antibiotocs that function through the new target have been identified: myxopyronin, corallopyronin, ripostatin, and lipiarmycin. This review summarizes the switch region, switch-region inhibitors, and implications for antibacterial drug discovery.

TFE and Spt4/5 open and close the RNA polymerase clamp during the transcription cycle

“…4). Early models have suggested that the clamp hinges in and out via the switch motifs orthogonal to the direction of transcription (14,63,64). However, recent structural models have suggested that the conformational changes are more sophisticated than that (35,36,65); a widening of the cleft can alternatively be achieved by a pivoting motion of the two large RNAP subunits against each other.…”

Novel Rapidly Diversifiable Antimicrobial RNA Polymerase Switch Region Inhibitors with Confirmed Mode of Action in Haemophilus influenzae

“…The antimicrobial activity against an efflux-negative strain of H. influenzae was exploited to show that squaramides mediate their inhibitory activity via the switch region of RNAP. Their mode of action therefore is similar to that of the natural compounds myxopyronin, corallopyronin, ripostatin, and fidaxomicin (26) rather than that of rifamycins, which bind closer to the catalytic site and prevent RNA extension (7). This is the first report of rapidly diversifiable small-molecule inhibitors of RNAP with that mode of inhibition, supporting the use of a transcription-coupled translation assay to find novel inhibitory scaffolds of the RNAP switch region in small-molecule collections.…”

Bacterial Transcription as a Target for Antibacterial Drug Development

“…It is worth noting that corallopyronin, which is structurally similar to the myxopyronins, as well as the structurally distinct ripostatin, demonstrated the same inhibitory activity on transcription initiation, and the amino acid substitutions that resulted in resistance to these molecules also overlapped (136)(137)(138). These results indicated that corallopyronin and ripostatin also bind to the switch region (132).…”

“…There is currently no published structure of fidaxomicin or lipiarmycin in complex with RNAP, but biochemical experiments indicated that both of these molecules bind to the switch region (136,145,146). Lipiarmycin did not prevent promoter binding but could inhibit promoter DNA melting and -dependent transcription, as well as template strand DNA binding to RNAP.…”