Chemical proteomics approaches for identifying the cellular targets of natural products

Wright, Megan H.; Sieber, Stephan A.

doi:10.1039/c6np00001k

Cited by 334 publications

(290 citation statements)

References 125 publications

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“…8 The ABPP-based isolation of enzymes by nonspecific probe labeling at residues not directly associated with the catalytic site is a known limitation of this technique. 18 …”

mentioning

confidence: 99%

ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance

et al. 2017

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Certain commensal Escherichia coli contain the clb biosynthetic gene cluster that codes for small molecule prodrugs known as precolibactins. Precolibactins are converted to colibactins by N-deacylation; the latter are postulated to be genotoxic and to contribute to colorectal cancer formation. Though advances toward elucidating (pre)colibactin biosynthesis have been made, the functions and mechanisms of several clb gene products remain poorly understood. Here we report the 2.1 Å X-ray structure and molecular function of ClbS, a gene product that confers resistance to colibactin toxicity in host bacteria and which has been shown to be important for bacterial viability. The structure harbors a potential colibactin binding site and shares similarity to known hydrolases. In vitro studies using a synthetic colibactin analog and ClbS or an active site residue mutant reveal cyclopropane hydrolase activity that converts the electrophilic cyclopropane of the colibactins into an innocuous hydrolysis product. As the cyclopropane has been shown to be essential for genotoxic effects in vitro, this ClbS-catalyzed ring-opening provides a means for the bacteria to circumvent self-induced genotoxicity. Our study provides a molecular-level view of the first reported cyclopropane hydrolase and support for a specific mechanistic role of this enzyme in colibactin resistance.

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“…8 The ABPP-based isolation of enzymes by nonspecific probe labeling at residues not directly associated with the catalytic site is a known limitation of this technique. 18 …”

mentioning

confidence: 99%

ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance

et al. 2017

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“…One strategy is to prepare chemical probes of 1 to screen for alternative targets. 51 Guided by molecular modeling and enabled by access to material, we will prepare analogs of 1 via total and semi-synthesis to improve biological activity and physicochemical properties. Another strategy is to perform whole-genome sequencing for albocycline-resistant mutants of S. aureus .…”

Section: Resultsmentioning

confidence: 99%

Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus

Liang

Zhou

et al. 2018

Bioorganic & Medicinal Chemistry

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Antibiotic resistance is a serious threat to global public health, and methicillin-resistant Staphylococcus aureus (MRSA) is a poignant example. The macrolactone natural product albocycline, derived from various Streptomyces strains, was recently identified as a promising antibiotic candidate for the treatment of both MRSA and vancomycin-resistant S. aureus (VRSA), which is another clinically relevant and antibiotic resistant strain. Moreover, it was hypothesized that albocycline's antimicrobial activity was derived from the inhibition of peptidoglycan (i.e., bacterial cell wall) biosynthesis. Herein, preliminary mechanistic studies are performed to test the hypothesis that albocycline inhibits MurA, the enzyme that catalyzes the first step of peptidoglycan biosynthesis, using a combination of biological assays alongside molecular modeling and simulation studies. Computational modeling suggests albocycline exists as two conformations in solution, and computational docking of these conformations to an ensemble of simulated receptor structures correctly predicted preferential binding to S. aureus MurA-the enzyme that catalyzes the first step of peptidoglycan biosynthesis-over Escherichia coli (E. coli) MurA. Albocycline isolated from the producing organism (Streptomyces maizeus) weakly inhibited S. aureus MurA (IC of 480 μM) but did not inhibit E. coli MurA. The antimicrobial activity of albocycline against resistant S. aureus strains was superior to that of vancomycin, preferentially inhibiting Gram-positive organisms. Albocycline was not toxic to human HepG2 cells in MTT assays. While these studies demonstrate that albocycline is a promising lead candidate against resistant S. aureus, taken together they suggest that MurA is not the primary target, and further work is necessary to identify the major biological target.

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“…[117][118][119][120][121] ABPP analysiert die direkte Interaktion von Liganden und ihren Zielproteinen (Abbildung 5a). [117][118][119][120][121] ABPP analysiert die direkte Interaktion von Liganden und ihren Zielproteinen (Abbildung 5a).…”

Section: Identifizierung Und Validierung Der Biologischen Zielstrukturunclassified

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

et al. 2018

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Die öffentliche Wahrnehmung von Antibiotika als verlässliche Arzneimittel veränderte sich drastisch, als Meldungen über “multiresistente Super‐Erreger” die Nachrichten aufrüttelten. Während die Ursachen für die bakterielle Resistenzentwicklung schnell erkannt wurden, befindet sich die Forschung zur Wiedergewinnung von Antibiotika als effektive Arzneistoffe immer noch am Anfang. Dieser Aufsatz umfasst zahlreiche Aspekte des Entwicklungsprozesses neuer Antibiotika, von der Grundlagenforschung bis zum fertigen Medikament. Er bietet einen interdisziplinären Überblick über Methoden zur Identifizierung neuer Antibiotika und erörtert Strategien, um ihren molekularen Wirkmechanismus aufzuklären. Die Darstellung ausgewählter Antibiotika, die kürzlich mithilfe dieser Plattformen entdeckt wurden, verdeutlicht die Effizienz der Ansätze und hebt vielversprechende klinische Kandidaten mit therapeutischem Potential hervor. Zusätzlich wird das Konzept von Molekülen erörtert, die Krankheitserreger “entwaffnen”, indem sie Schlüsselpunkte der Virulenz adressieren. Der Aufsatz schließt mit einer kritischen Beurteilung jener antibakteriellen Wirkstoffe, die sich derzeit in klinischer Entwicklung befinden. Insgesamt soll dieser Aufsatz ausgewählte, innovative antibakterielle Ansätze verknüpfen, um interdisziplinäre Partnerschaften zwischen Chemikern aus der akademischen und industriellen Forschung anzuregen.

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Chemical proteomics approaches for identifying the cellular targets of natural products

Abstract: This review focuses on chemical probes to identify the protein binding partners of natural products in living systems.

Cited by 334 publications

References 125 publications

ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance

ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance

Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

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