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Target and method for inhibition of bacterial rna polymerase

a technology of rna polymerase and target, which is applied in the direction of biological material analysis, peptides, drug compositions, etc., can solve the problems of grave and growing threat to public health infection

Inactive Publication Date: 2006-07-20
EBRIGHT RICHARDH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] Applicant has discovered that a region within the secondary channel comprising two adjacent short peptide segments of the RNAP β′ subunit are conserved in amino-acid sequence in bacterial species, including both Gram-positive bacteria and Gram-negative bacteria. Throughout the following specification, this region is referred to as the “β′ pocket” or the “target,” and the two short peptide segments are referred to as “homologous secondary channel amino acids or amino acid sequences.” Applicant has also discovered that this same region is not conserved, and in fact is radically different, in amino-acid sequence in eukaryotic RNAP, such as human RNAP I, RNAP II, and RNAP III.

Problems solved by technology

Multi-drug-resistant bacteria now cause infection that poses a grave and growing threat to public health.
Unfortunately, tuberculosis strains resistant to rifampicin (and rifampicin analogs) are becoming widespread, effectively removing rifampicin from the therapeutic arsenal.

Method used

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  • Target and method for inhibition of bacterial rna polymerase
  • Target and method for inhibition of bacterial rna polymerase
  • Target and method for inhibition of bacterial rna polymerase

Examples

Experimental program
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Effect test

example 1

Cyclic Peptide MCCJ25 (MCCJ25) Inhibits Transcription by Obstructing the RNAP Secondary Channel

Introduction:

[0113] The cyclic-peptide antibiotic MccJ25 (MccJ25) inhibits transcription by Escherichia coli RNA polymerase (RNAP) in a purified system. Biochemical results indicate that MccJ25 inhibits the abortive-initiation and elongation phases of transcription. Kinetic results indicate that MccJ25 inhibits transcription by interfering with NTP uptake. Genetic results indicate that MccJ25 inhibits transcription through interactions with an extensive determinant, comprising nearly fifty amino acid residues, within the RNAP secondary channel (also known as the secondary channel or pore). MccJ25 inhibits transcription by binding within, and obstructing, the RNAP secondary channel—acting essentially as a “cork in a bottle.” Obstruction of the RNAP secondary channel represents a novel mechanism of inhibition and an attractive target for drug discovery.

[0114] MccJ25 (MccJ25) is a 21 resi...

example 2

Probe-Labelled Derivatives of Peptide Antibiotic MccJ25

[0146] One aspect of the invention provides probe-labelled derivatives of the peptide antibiotic MccJ25 (MccJ25). The invention has broad applications in analysis of RNAP structure and function, control of bacterial gene expression, control of bacterial growth, antibacterial chemistry, antibacterial therapy, and drug discovery.

[0147] The present invention also provides a composition comprising a compound according to the general structural formula (I): J-Z-X, wherein J is MccJ25 or a substituted and / or truncated derivative thereof, Z is a covalent linker or is absent, and X is a detectable group. One aspect of the present invention, provides a composition comprising a compound according to the general structural formula (I) wherein X is selected from the group consisting of a fluorescent moiety, a phosphorescent moiety, a luminescent moiety, an absorbent moiety, a photosensitizer, a spin label, a radioisotope, an isotope detec...

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Abstract

Target and method for inhibition of bacterial RNA polymerase disclosed are targets and methods for specific binding and inhibition of RNAP from bacterial species. Bacterial RNA polymeraseRPOC_ECOLI (736) QIRQLAGMRGLM (779) ARKRPOC_HAEIN (737) QIRQLAGMRGLM (780) ARKRPOC_VIBCH (736) QIRQLAGMRGLM (779) ARKRPOC_PSEAE (736) QIRQLAGMRGLM (779) ARKRPOC_TREPA (703) QIRQLAGMRGLM (746) ARKRPOC_BORBU (699) QIRQLAGMRGLM (742) ARKRPOC_XYLFA (759) QIRQLAAMRGLM (802) ARKRPOC_CAMJE (734) QISQLAAMRGLM (777) ARKRPOC_NEIMA (738) QIKQLSGMRGLM (781) ARKRPOC_RICPR (730) QIKQLGGMRGLM (773) MRKRPOC_THEMA(1010) QVKQLAGIRGLM(1072) ARKRPOC_CHLTR (736) QLKQLGALRGLM (779) ARKRPOC_MYCPN (820) NFTQLFGMRGLM (874) ARKRPOC_BACSU (740) NFTQLAGMRGLM (783) ARKRPOC_STAAU (744) NFTQLAGMRGLM (787) ARKRPOC_MYCTU (813) QTRTLAGMKGLV (856) ARKRPOC_SYNY3 (763) QVRQLVGMRGLM (806) ARKRPOC_AQUAE (850) QIRQLAGMRGLM (893) ARKRPOC_DEIRA(1052) QIRQLAGMRGLM(1095) ARKRPOC_TTHER(1034) QIRQLCGLRGLM(1077) ARKRPOC_THEAQ(1034) QIRQLCGMRGLM(1077) ARKHuman RNA polymerases I,II, and IIIRPA1_HUMAN (908) NTMQISCLLGQI (971) GRERPB1_HUMAN (780) NISQVIAVVGQQ (843) GRERPC1_HUMAN (791) NISQMIACVGQQ (854) GRE

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to provisional applications: 60 / 407,684 filed Sep. 4, 2002; 60 / 474,607 filed on Jun. 2, 2003; and 60 / 474,608 filed on Jun. 2, 2003, the contents of which are incorporated herein by reference.GOVERNMENT SUPPORT [0002] This invention was supported with U.S. Government funds (NIH RO1-GM41376). Therefore, the Government may have rights in the invention.BACKGROUND ART [0003] Bacterial infections remain among the most common and deadly causes of human disease. Infectious diseases are the third leading cause of death in the United States and the leading cause of death worldwide (Binder et al., Science 284:1311-1313 (1999)). Multi-drug-resistant bacteria now cause infection that poses a grave and growing threat to public health. It has been shown that bacterial pathogens can acquire resistance to first-line and even second-line antibiotics. (See, Stuart B. Levy, The Challenge of Antibiotic Resistance, in Scienti...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/554A61K38/16C07K14/32C07H21/04C07K14/245
CPCC07K14/245G01N33/502G01N33/533G01N33/569G01N2500/00
Inventor EBRIGHT, RICHARDH
Owner EBRIGHT RICHARDH
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