Chemical and Microbiologic Aspects of Penems, a Distinct Class of β‐Lactams: Focus on Faropenem

Hamilton‐Miller, J. M. T.

doi:10.1592/phco.23.14.1497.31937

Cited by 41 publications

(20 citation statements)

References 41 publications

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“…It is noteworthy that tazobactam and sulbactam demonstrated a modest ability to inhibit ADC-7 ␤-lactamase activity (5, 9). Sulopenem, a penem antibiotic that combines features of penicillin and cephalosporins, also has a low K i against ADC-7 ␤-lactamase (15,17). The singular property of carbapenems, sulfones, and penems to serve as inhibitors of penicillin binding proteins and class C enzymes merits consideration.…”

Section: Resultsmentioning

confidence: 99%

Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase, ADC-7 β-Lactamase: Defining a Unique Family of Class C Enzymes

Hujer¹,

Hamza

Hujer³

et al. 2005

Antimicrob Agents Chemother

142

138

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Acinetobacter spp. are emerging as opportunistic hospital pathogens that demonstrate resistance to many classes of antibiotics. In a metropolitan hospital in Cleveland, a clinical isolate of Acinetobacter baumannii that tested resistant to cefepime and ceftazidime (MIC ‫؍‬ 32 g/ml) was identified. Herein, we sought to determine the molecular basis for the extended-spectrum-cephalosporin resistance. Using analytical isoelectric focusing, a ␤-lactamase with a pI of >9.2 was detected. PCR amplification with specific A. baumannii cephalosporinase primers yielded a 1,152-bp product which, when sequenced, identified a novel 383-amino-acid class C enzyme. Expressed in Escherichia coli DH10B, this ␤-lactamase demonstrated greater resistance against ceftazidime and cefotaxime than cefepime (4.0 g/ml versus 0.06 g/ml). The kinetic characteristics of this ␤-lactamase were similar to other cephalosporinases found in Acinetobacter spp. In addition, this cephalosporinase was inhibited by meropenem, imipenem, ertapenem, and sulopenem (K i < 40 M). The amino acid compositions of this novel enzyme and other class C ␤-lactamases thus far described for A. baumannii, Acinetobacter genomic species 3, and Oligella urethralis in Europe and South Africa suggest that this cephalosporinase defines a unique family of class C enzymes. We propose a uniform designation for this family of cephalosporinases (Acinetobacter-derived cephalosporinases [ADC]) found in Acinetobacter spp. and identify this enzyme as ADC-7 ␤-lactamase. The coalescence of Acinetobacter ampC ␤-lactamases into a single common ancestor and the substantial phylogenetic distance separating them from other ampC genes support the logical value of developing a system of nomenclature for these Acinetobacter cephalosporinase genes.Acinetobacter spp. are commonly associated with serious nosocomial infections (10,14,23,37,40,41). Most recently, American troops wounded in Iraq (Operation Iraqi Freedom) and Afghanistan (Operation Enduring Freedom) have suffered severe infections from antibiotic-resistant Acinetobacter baumannii, making this organism an important pathogen in military health

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Section: Resultsmentioning

confidence: 99%

Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase, ADC-7 β-Lactamase: Defining a Unique Family of Class C Enzymes

Hujer¹,

Hamza

Hujer³

et al. 2005

Antimicrob Agents Chemother

142

138

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“…Them onobactam Lys-228 from Novartis is in phase Idevelopment. [296,297] Cefiderocol (phase III) from Shionogi is an innovative b-lactam which incorporates a2 -chloro-3,4-dihydroxybenzoyl siderophore. [294,295] It has ab road activity against Gramnegative bacteria, with the exception of P. aeruginosa.…”

Section: B-lactam Antibioticsmentioning

confidence: 99%

“…Sulopenem as well as its orally available prodrug sulopenem etzadroxil are in phase II studies and show activity for Enterobacteriaceae that produce ESBLs. [296,297] Cefiderocol (phase III) from Shionogi is an innovative b-lactam which incorporates a2 -chloro-3,4-dihydroxybenzoyl siderophore. [298,299] As a" Tr ojan horse", the antibiotic mimics substrates of cognate iron transport and thereby facilitates penetration of the outer membrane of Gram-negative bacteria.…”

Section: B-lactam Antibioticsmentioning

confidence: 99%

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

et al. 2018

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The public view on antibiotics as reliable medicines changed when reports about "resistant superbugs" appeared in the news. While reasons for this resistance development are easily spotted, solutions for re-establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary overview is given of methods suitable for mining novel antibiotics and strategies discussed to unravel their modes of action. Select examples of antibiotics recently identified by using these platforms not only illustrate the efficiency of these measures, but also highlight promising clinical candidates with therapeutic potential. Furthermore, the concept of molecules that disarm pathogens by addressing gatekeepers of virulence will be covered. The Review concludes with an evaluation of antibacterials currently in clinical development. Overall, this Review aims to connect select innovative antimicrobial approaches to stimulate interdisciplinary partnerships between chemists from academia and industry.

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“…Sulopenem und dessen oral verfügbarer Arzneistoff-Vorläufer Sulopenem Etzadroxil befinden sich in Phase II und zeigen Wirksamkeit gegenüber ESBL-produzierenden Enterobacteriaceae. [296,297] Cefiderocol (Phase III) von Shionogi ist ein innovatives b-Lactam, welches einen 2-Chlor-3,4-dihydroxybenzoyl-Siderophor enthält. [298,299] Vergleichbar mit einem Tr ojanischen Pferd imitiert dieses Antibiotikum Substrate des bakterieneigenen Eisentransports und ermçglicht so das Eindringen in die äußere Membran des…”

Section: B-lactam-antibiotikaunclassified

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 and Microbiologic Aspects of Penems, a Distinct Class of β‐Lactams: Focus on Faropenem

Cited by 41 publications

References 41 publications

Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase, ADC-7 β-Lactamase: Defining a Unique Family of Class C Enzymes

Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase, ADC-7 β-Lactamase: Defining a Unique Family of Class C Enzymes

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

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

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