A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1

Arhin, Francis F.; Bélanger, Odette; Ciblat, Stéphane; Dehbi, Mohammed; Delorme, Daniel; Dietrich, Evelyne; Dixit, Dilip M.; Lafontaine, Yanick; Lehoux, Dario; Liu, Jing; McKay, Geoffrey A.; Moeck, Greg; Reddy, Ranga; Rose, Yannick; Srikumar, Ramakrishnan; Tanaka, Kelly S.E.; Williams, Daniel M.; Gros, Philippe; Parr, Thomas; Far, Adel Rafai

doi:10.1016/j.bmc.2006.05.035

Cited by 37 publications

(35 citation statements)

References 23 publications

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“…The filtrate was concentrated and the resulting residue purified on silica gel eluting with ethyl acetate, followed by a gradient of 0 to 10% methanol in dichloromethane, to give the title compound as a yellow oil (2.07 g, 6.89 mmol, 47.5% yield). 1 25 mmol), and diisopropylethylamine (0.75 ml) in 1,4-dioxane (8 ml) was heated to 60°C for 18 h. Solvents were removed under reduced pressure, and the resulting oil was purified by silica gel chromatography, eluting a linear gradient of 50 to 100% acetone in ethyl acetate. The desired product was then precipitated from a hot ethyl acetate hexane mixture to give the title compound as an off-white powder (58 mg, 53% yield).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2012

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A series of inhibitors with a squaramide core was synthesized following its discovery in a high-throughput screen for novel inhibitors of a transcription-coupled translation assay using Escherichia coli S30 extracts. The inhibitors were inactive when the plasmid substrate was replaced with mRNA, suggesting they interfered with transcription. This was confirmed by their inhibition of purified E. coli RNA polymerase. The series had antimicrobial activity against efflux-negative strains of E. coli and Haemophilus influenzae. Like rifampin, the squaramides preferentially inhibited synthesis of RNA and protein over fatty acids, peptidoglycan, and DNA. However, squaramide-resistant mutants were not cross-resistant to rifampin. Nine different mutations were found in parts of rpoB or rpoC that together encode the so-called switch region of RNA polymerase. This is the binding site of the natural antibiotics myxopyronin, corallopyronin, and ripostatin and the drug fidaxomicin. Computational modeling using the X-ray crystal structure of the myxopyronin-bound RNA polymerase of Thermus thermophilus suggests a binding mode of these inhibitors that is consistent with the resistance mutations. The squaramides are the first reported non-natural-productrelated, rapidly diversifiable antibacterial inhibitors acting via the switch region of RNA polymerase. C linical resistance to currently prescribed antibiotics is on the rise, thus increasing the need for new classes of antimicrobials that can circumvent emerging resistance mechanisms (10). There are still only a few enzymes that are essential for bacterial growth and have been clinically validated as antibacterial targets. All clinical antibacterial protein translation inhibitors have so far been identified by cell-based screening efforts with compounds from natural sources (8). New, small inhibitors might be found by screening small-molecule libraries for inhibitors of the translation machinery with an in vitro system, such as transcription-coupled translation in bacterial S30 extracts.Here, we report the discovery of squaramides as inhibitors of RNA polymerase (RNAP) that resulted from such a screening effort. 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. MATERIALS AND METHODSBacterial strains. E. coli RNAP and S30 extracts were isolated from E. coli MRE600 (ATCC 2941). For susceptibility studies E. coli ATCC 27325 and H. influenzae ATCC 51907 ...

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Section: Methodsmentioning

confidence: 99%

“…The desired product was then precipitated from a hot ethyl acetate hexane mixture to give the title compound as an off-white powder (58 mg, 53% yield). 1 …”

Section: Methodsmentioning

confidence: 99%

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

et al. 2012

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“…Ureidothiophene was discovered though chemical library screening against S. aureus RNAP holoenzyme and demonstrated good antibacterial activity against Gram-positive bacteria, including S. aureus and S. epidermidis (147). However, mammalian albumin binds tightly to ureidothiophene, eliminating its in vivo activity.…”

Section: Inhibitors With Unknown Targetsmentioning

confidence: 99%

Bacterial Transcription as a Target for Antibacterial Drug Development

Yang

Lewis

2016

Microbiol Mol Biol Rev

107

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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%

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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A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1

Cited by 37 publications

References 23 publications

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

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

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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