Novel synthetic molecules targeting the bacterial RNA polymerase assembly

André, Estelle; Bastide, Lionel; Michaux‐Charachon, Sylvie; Gouby, A.; Villain-Guillot, Philippe; Latouche, Jaqueline; Bouchet, Aurélie; Gualtieri, Maxime; Leonetti, Jean-Paul

doi:10.1093/jac/dki426

Cited by 48 publications

(41 citation statements)

References 24 publications

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“…Using an enzyme-linked immunosorbent assay (ELISA)-based approach, the Leonetti group has screened a library of small molecules for inhibitors of the assembly of 70 onto the RNAP core (8). Several inhibitors of holoenzyme assembly on May 9, 2018 by guest http://mmbr.asm.org/ were identified, with some demonstrating bactericidal activity, particularly against Gram-positive organisms.…”

Section: Architecture Of Transcription Complexes and Suitability For mentioning

confidence: 99%

Essential Biological Processes of an Emerging Pathogen: DNA Replication, Transcription, and Cell Division in Acinetobacter spp

Robinson

Brzoska

Turner

et al. 2010

Microbiol Mol Biol Rev

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SUMMARY Within the last 15 years, members of the bacterial genus Acinetobacter have risen from relative obscurity to be among the most important sources of hospital-acquired infections. The driving force for this has been the remarkable ability of these organisms to acquire antibiotic resistance determinants, with some strains now showing resistance to every antibiotic in clinical use. There is an urgent need for new antibacterial compounds to combat the threat imposed by Acinetobacter spp. and other intractable bacterial pathogens. The essential processes of chromosomal DNA replication, transcription, and cell division are attractive targets for the rational design of antimicrobial drugs. The goal of this review is to examine the wealth of genome sequence and gene knockout data now available for Acinetobacter spp., highlighting those aspects of essential systems that are most suitable as drug targets. Acinetobacter spp. show several key differences from other pathogenic gammaproteobacteria, particularly in global stress response pathways. The involvement of these pathways in short- and long-term antibiotic survival suggests that Acinetobacter spp. cope with antibiotic-induced stress differently from other microorganisms.

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Section: Architecture Of Transcription Complexes and Suitability For mentioning

confidence: 99%

Essential Biological Processes of an Emerging Pathogen: DNA Replication, Transcription, and Cell Division in Acinetobacter spp

Robinson

Brzoska

Turner

et al. 2010

Microbiol Mol Biol Rev

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“…These compounds could inhibit E. coli 70 binding to RNAP with an IC 50 of 2 to 15 M, although their binding site was unknown. The -independent transcription inhibition activity of the SB series suggested that the compound binding site was on RNAP rather than (186).…”

Section: The Rnap-interactionmentioning

confidence: 99%

Bacterial Transcription as a Target for Antibacterial Drug Development

Yang

Lewis

2016

Microbiol Mol Biol Rev

104

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SUMMARYTranscription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

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“…Thus, CBR703 and CBR64 have a bactericidal activity against persister bacteria. The bacterial RNAP is a good target for the development of new bactericidal antibiotics, as is highlighted by the recent publication of three new synthetic inhibitors (2)(3)(4). In the present study we have compared clinically used molecules with excellent pharmacological properties to natural molecules and the latest synthetic inhibitors of transcription to determine whether this enzyme is truly of interest to generate new drugs that are active on biofilms.…”

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confidence: 99%

“…24 h-biofilm, log 10 (CFU) ϭ 0.90 ϫ log 10 (RLU) ϩ 0.85, R 2 ϭ 0.9994 (1) 48 h-biofilm, log 10 (CFU) ϭ 0.96 ϫ log 10 (RLU) ϩ 0.53, R 2 ϭ 0.9997 (2) Since no significant difference was observed between these equations, equation 1 was used to assess the amount of embedded bacteria within challenged and unchallenged biofilms. Quantification of persister bacteria within the biofilm.…”

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confidence: 99%

In Vitro Activities of Different Inhibitors of Bacterial Transcription against Staphylococcus epidermidis Biofilm

Villain-Guillot

Gualtieri

Bastide³

et al. 2007

Antimicrob Agents Chemother

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Staphylococcus epidermidis is a major cause of nosocomial infections because of its ability to form biofilms on the surface of medical devices. Only a few antibacterial agents are relatively active against biofilms, and rifampin, a transcription inhibitor, ranks among the most effective molecules against biofilm-related infections. Whether this efficacy is due to advantageous structural properties of rifampin or to the fact that the RNA polymerase is a favorable target remains unclear. In an attempt to answer this question, we investigated the action of different transcription inhibitors against S. epidermidis biofilm, including the newest synthetic transcription inhibitors. This comparison suggests that most of the antibiotics that target the RNA polymerase are active on S. epidermidis biofilms at concentrations close to their MICs. One of these compounds, CBR703, despite its high MIC ranks among the best antibiotics to eradicate biofilm-embedded bacteria.

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Novel synthetic molecules targeting the bacterial RNA polymerase assembly

Abstract: This is, to our knowledge, the first example of a small molecule inhibitor of this interaction.

Cited by 48 publications

References 24 publications

Essential Biological Processes of an Emerging Pathogen: DNA Replication, Transcription, and Cell Division in Acinetobacter spp

Essential Biological Processes of an Emerging Pathogen: DNA Replication, Transcription, and Cell Division in Acinetobacter spp

Bacterial Transcription as a Target for Antibacterial Drug Development

In Vitro Activities of Different Inhibitors of Bacterial Transcription against Staphylococcus epidermidis Biofilm

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