Antibiotikaresistenzen gezielt überwinden

Chellat, Mathieu F.; Raguž, Luka; Riedl, Rainer

doi:10.1002/ange.201506818

Cited by 34 publications

(8 citation statements)

References 201 publications

(231 reference statements)

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“…4) [29]. Außerdem wechselten wir von Imipenem auf die Analyse von Gentamicin, das selbst auch Membran-modifizierende Eigenschaften aufweist [2].…”

Section: Einfluss Von Eugenol Und Lysozym Auf Die Wirkung Von Imipenem Gegenüber K Pneumoniaeunclassified

“…Werden diese in die Zellmembran eingebaut, führt dies zu einer Erhöhung der Membranpermeabilität. Die gesteigerte Membranpermeabilität führt in der nächsten Phase zu einem erhöhten Aminoglykosid-Influx, der dann die Proteinsynthese so stark beeinflusst, dass es zum Absterben des Bakteriums kommt [2]. Das Zimtöl, das bereits unterhalb der MHK Zellmembran-modulierende Eigenschaften aufweist [27], könnte zu einem erhöhten initialen Aminoglykosid-Influx führen.…”

Section: Einfluss Von Eugenol Und Lysozym Auf Die Wirkung Von Imipenem Gegenüber K Pneumoniaeunclassified

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Ätherische Öle aus Zimt und Gewürznelken verstärken die Wirkung von Antibiotika gegen multiresistente bakterielle Krankheitserreger

Sakr

Schmidt

Bereswill

et al. 2021

Zeitschrift für Phytotherapie

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ZusammenfassungDie Häufigkeit bakterieller Infektionen, bei denen Antibiotika nicht mehr wirken, steigt aufgrund der Resistenzentwicklung der Krankheitserreger weltweit. Um dieser Bedrohung zu begegnen, werden – neben der Entwicklung neuer Antibiotika und der Reaktivierung bereits vorhandener antibakterieller Wirkstoffe – auch die Resistenz-modifizierenden Eigenschaften von Naturstoffen erforscht. In der vorliegenden Arbeit wurde mit dem Checkerboard-Mikrodilutionsverfahren untersucht, wie die ätherischen Öle aus Gewürznelken (Syzygium aromaticum) und der Rinde des Zimtbaums (Cinnamomum verum) kombiniert mit Lysozym die Wirkungen von Antibiotika aus der Gruppe der Carbapeneme (Imipenem) und der Aminoglykoside (Gentamicin) gegen die bakteriellen Krankheitserreger Pseudomonas aeruginosa bzw. Klebsiella pneumoniae verstärken. Die Ergebnisse zeigen, dass die ätherischen Öle beider Pflanzenarten die minimalen Hemmkonzentrationen von Gentamicin und Imipenem gegenüber multiresistenten klinischen Isolaten der beiden gramnegativen Bakterienarten vermindern und damit die Antibiotikawirkung signifikant steigern. Die potenten Resistenz-modifizierenden Eigenschaften der ätherischen Öle lassen weitere Untersuchungen der Phenylpropanoide als Hauptkomponenten beider Öle und anderer Naturstoffe in diesem Kontext vielversprechend erscheinen.

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“…4) [29]. Außerdem wechselten wir von Imipenem auf die Analyse von Gentamicin, das selbst auch Membran-modifizierende Eigenschaften aufweist [2].…”

Section: Einfluss Von Eugenol Und Lysozym Auf Die Wirkung Von Imipenem Gegenüber K Pneumoniaeunclassified

Ätherische Öle aus Zimt und Gewürznelken verstärken die Wirkung von Antibiotika gegen multiresistente bakterielle Krankheitserreger

Sakr

Schmidt

Bereswill

et al. 2021

Zeitschrift für Phytotherapie

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“…Dual targeting of GyrB and structurally similar topoisomerase IV ParE subunits has been suggested to prolong the onset of resistance in bacteria because mutations at both essential sites are less probable than single mutations at GyrB or ParE ATP‐binding sites . This observation evoked our interest in the design and preparation of the first dual inhibitors of GyrA and GyrB that could open new avenues for DNA gyrase inhibition and fighting bacterial resistance …”

Section: Figurementioning

confidence: 99%

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

et al. 2019

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The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report firstin-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.Bacterial DNA gyrase, a type IIa topoisomerase responsible for ATP-driven introduction of negative supercoils into DNA, [1] is a well-established target of antibacterials. [2] Whereas fluoroquinolones targeting the GyrA subunit of a heterodimeric A 2 B 2 enzyme are widely used to treat infections with gram-positive and gram-negative bacteria, [2b,d,3] GyrB inhibitors interfering with ATP binding to subunit B have not advanced into the clinic despite intensive research over the last 50 years after the discovery of novobiocin as the first ATP-competitive GyrB inhibitor in the 1960s. [2f-h] We recently reported several structural types of low-nanomolar pyrrole-2-carboxamide GyrB inhibitors [4][5][6] and established the binding mode of 2-((2-(4,5dibromo-1H-pyrrole-2-carboxamido)benzo[d]thiazol-6-yl) amino)-2-oxoacetic acid (1 a; IC 50 E. coli = 58 nM), [6] a 4,5dibromo-pyrrole analog of 1 b (IC 50 E.coli = 43 nM), [7] to GyrB from E. coli with X-ray crystallography. However, most of these inhibitors were devoid of in vitro antibacterial activity because of insufficient permeation and/or extrusion by bacterial efflux pumps. [6,7] Dual targeting of GyrB and structurally similar topoisomerase IV ParE subunits has been suggested to prolong the onset of resistance in bacteria because mutations at both essential sites are less probable than single mutations at GyrB or ParE ATP-binding sites. [2g,8a] This observation evoked our interest in the design and preparation of the first dual inhibitors of GyrA and GyrB that could open new avenues for DNA gyrase inhibition and fighting bacterial resistance. [8b] Designed multiple ligands can be obtained by linking, merging or fusing individual pharmacophores in a way tolerated by respective targets. [9] Several 4-quinolone hybrids with trimethoprim, [10a] linezolid, [10b] and tobramycin [10c] were obtained, and these as well as other studies [11] demonstrated that moieties of different sizes attached to the piperazine NH grou...

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“…1,2 The Lewis acidity of the boron and its easy conversion from trigonal to tetrahedral geometry enables benzoxaboroles to bind to the active site of various enzymes and thereby inhibit their activity. 1,3 Ever since the discovery of the exceptional sugar-binding properties at physiological conditions 4 as well as the finding of antifungal activity of AN2690 (Fig. 1), 5 benzoxaboroles have been extensively studied for therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

“…This leads to the development of benzoxaboroles with antibacterial, 6 antiviral, 7 anti-parasitic, 8 anti-inflammatory, 9 and antimalarial 10 activities as well as β-lactamase inhibitor. 1 …”

Section: Introductionmentioning

confidence: 99%