Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase

Maffioli, Sonia; Zhang, Yu; Degen, David; Carzaniga, Thomas; Gatto, Giancarlo Del; Serina, Stefania; Monciardini, Paolo; Mazzetti, Carlo; Guglierame, Paola; Candiani, Gianpaolo; Chiriac, Alina Iulia; Facchetti, Giuseppe; Kaltofen, Petra; Sahl, Hans‐Georg; Dehò, Gianni; Donadio, Stefano; Ebright, Richard H.

doi:10.1016/j.cell.2017.05.042

Cited by 124 publications

(203 citation statements)

References 80 publications

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“…The third key finding is that we discovered PUM by screening microbial extracts [1]. Microbial-extract screening has not been exhausted as a source of new antibacterial compounds.…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

“…Apropos combination therapy and PUM, we showed in our paper that administering a combination of PUM and a rifamycin suppresses the emergence of resistance by multiple orders of magnitude, to levels below the limit of detection [1]. Combination therapy works, both in general and for PUM in particular.…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

“…Should it be used in combination therapy? Resistance to PUM arises, but it arises in an order of magnitude less frequently than resistance to current antibacterial drugs that target bacterial RNA polymerase [1].…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

“…The second key finding is that PUM functions as a 'nucleoside-analog inhibitor' of bacterial RNA polymerase [1], meaning that PUM functions by mimicking an NTP. PUM binds to the NTP binding pocket within the RNA polymerase nucleotide-addition site, and, by occupying the NTP binding pocket, PUM prevents NTPs from binding and being used for RNA synthesis.…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

“…PUM is a new antibiotic effective against drug-resistant bacteria [1]. PUM is produced by a microbe found in a soil sample collected in Italy (a soil sample collected under one of the cypress trees in the famous Viale de Cipressi between Bolgheri and San Guido in Tuscany) and was discovered by systematically screening microbes from soil samples.…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

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Novel Rna Polymerase Inhibitor Found in Soil Extracts Provides Hope for Future Antibacterial Drugs

Ebright

2017

Future Med. Chem.

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" the rationale for the PUM project was to seek inhibitors of bacterial RNA polymerase that function through the nucleotide-addition site in order to take advantage of its predicted low propensity for resistance, and to do so by screening microbial-extract libraries to identify inhibitors of bacterial RNA polymerase and mutationally de-replicating hits, rapidly identifying those that are new compounds and that function through the nucleotide addition site. "Richard H Ebright talks to Rachel Coleby, Commissioning Editor: Ebright is at Rutgers University (New Brunswick, NJ, USA), where he performs research on the structure, mechanism, and regulation of bacterial transcription and on antibacterial drug discovery targeting bacterial transcription. He has received research awards, including the Searle Scholar Award, the Walter J Johnson Prize, the Schering-Plough Award of the American Society for Biochemistry and Molecular Biology, the Waksman Award of the Theobold Smith Society, the MERIT Award of the National Institutes of Health, and membership in the American Academy of Arts and Science. He has more than 130 publications in peer-reviewed journals and more than 30 issued and pending patents. What are the topics & research projects that you are working on in your lab currently? One half of my lab performs basic research on the structure and mechanism of bacterial RNA polymerase. RNA polymerase is a 'molecular machine' that carries out a complex series of reactions in transcription initiation, elongation, and termination. We use tools of structural biology, including x-ray crystallography and, recently, cryoelectron microscopy, to determine structures of bacterial RNA polymerase in different functional states, and we use tools of single-molecule biophysics, including single-molecule fluorescence and single-molecule nanomanipulation with magnetic tweezers and nanopore tweezers, to monitor transitions between functional states.The other half of my lab uses information from our and our colleagues' work on the structure and function of bacterial RNA polymerase to develop new antibacterial compounds that target RNA polymerase, seeking new antibacterial drugs that kill bacteria resistant to current antibacterial drugs. Four features of bacterial RNA

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“…The third key finding is that we discovered PUM by screening microbial extracts [1]. Microbial-extract screening has not been exhausted as a source of new antibacterial compounds.…”

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

Section: Can You Tell Us the Key Findings Of This Pseudouridimycin Prmentioning

confidence: 99%

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Novel Rna Polymerase Inhibitor Found in Soil Extracts Provides Hope for Future Antibacterial Drugs

Ebright

2017

Future Med. Chem.

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Pseudouridimycin: das erste Nukleosid‐Analogon, das bakterielle RNA‐Polymerase selektiv inhibiert

Chellat¹,

Riedl²

2017

Angewandte Chemie

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Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Agnello¹,

Brand²,

Chellat³

et al. 2019

Angewandte Chemie

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Das natürliche Phänomen der Wirkstoffresistenz stellt eine universelle Beeinträchtigung des Nutzens von pharmazeutischen Wirkstoffen in vielen klinischen Indikationen dar. Antibakterielle und antifungale Wirkstoffe sind dabei ebenso betroffen wie Wirkstoffe zur Behandlung von Krebs, Virusinfektionen oder durch Parasiten hervorgerufene Erkrankungen. Trotz der unterschiedlichen biologischen Zielstrukturen und Organismen, die bei der Entwicklung von Wirkstoffresistenzen involviert sind, konnten grundlegende molekulare Prozesse identifiziert werden, die zum Verständnis des Auftretens von Resistenzen beitragen und die Bekämpfung dieser nachteiligen Mechanismen erlauben. Strukturelle Informationen über die Prinzipien von Wirkstoffresistenzen sind heute vielfältig vorhanden, sodass neue Wirkstoffe entwickelt werden können, die weniger anfällig gegenüber einer Resistenzbildung sein werden. Dieser wissensbasierte Ansatz ist eine Grundlage für den Kampf gegen das unvermeidbare Auftreten von Wirkstoffresistenzen.

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Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase

Cited by 124 publications

References 80 publications

Novel Rna Polymerase Inhibitor Found in Soil Extracts Provides Hope for Future Antibacterial Drugs

Novel Rna Polymerase Inhibitor Found in Soil Extracts Provides Hope for Future Antibacterial Drugs

Pseudouridimycin: das erste Nukleosid‐Analogon, das bakterielle RNA‐Polymerase selektiv inhibiert

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

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