Abstract:
:The number of bacterial strains that are resistant against antibiotics increased dramatically during the past decades. This fact stresses the urgent need for the development of new antibacterial agents with novel modes of action targeting essential enzymes such as RNA polymerase (RNAP). Bacterial RNAP is a large multi-subunit complex consisting of a core enzyme (subunits: α(2)ββ'ω) and a dissociable sigma factor (σ(70); holo enzyme: α(2)ββ'ωσ(70)) that is responsible for promoter recognition and transcription initiation. The interface between core RNAP and σ(70) represents a promising binding site. Nevertheless, detailed studies investigating its druggability are rare. Compounds binding to this region could inhibit this protein-protein interaction and thus holo enzyme formation, resulting in inhibition of transcription initiation. Sixteen peptides covering different regions of the Escherichia coli σ(70):core interface were designed; some of them-all derived from σ(70) 2.2 region-led to a strong RNAP inhibition. Indeed, an ELISA-based experiment confirmed the most active peptide P07 to inhibit the σ(70):core interaction. Furthermore, an abortive transcription assay revealed that P07 impedes transcription initiation. In order to study the mechanism of action of P07 in more detail, molecular dynamics simulations and a rational amino acid replacement study were performed, leading to the conclusion that P07 binds to the coiled-coil region in β' and that its flexible N-terminus inhibits the enzyme by interaction with the β' lid-rudder-system (LRS). This work revisits the β' coiled-coil as a hot spot for the protein-protein interaction inhibition and expands it by introduction of the LRS as target site.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Hüsecken K,Negri M,Fruth M,Boettcher S,Hartmann RW,Haupenthal Jdoi
10.1021/cb3005758subject
Has Abstractpub_date
2013-04-19 00:00:00pages
758-66issue
4eissn
1554-8929issn
1554-8937journal_volume
8pub_type
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