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NICOLO' SANTI
Assegnista di ricerca
Dipartimento Scienze della Vita sede ex Scienze Farmaceutiche Via Campi 103
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Pubblicazioni
2023
- Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum
[Articolo su rivista]
Powers, R. A.; June, C. M.; Fernando, M. C.; Fish, E. R.; Maurer, O. L.; Baumann, R. M.; Beardsley, T. J.; Taracila, M. A.; Rudin, S. D.; Hujer, K. M.; Hujer, A. M.; Santi, N.; Villamil, V.; Introvigne, M. L.; Prati, F.; Caselli, E.; Bonomo, R. A.; Wallar, B. J.
abstract
Class C Acinetobacter-derived cephalosporinases(ADCs) represent an important target for inhibition in the multidrug-resistantpathogen Acinetobacter baumannii. ManyADC variants have emerged, and characterization of their structuraland functional differences is essential. Equally as important is thedevelopment of compounds that inhibit all prevalent ADCs despite thesedifferences. The boronic acid transition state inhibitor, MB076, a novel heterocyclic triazole with improved plasma stability, wassynthesized and inhibits seven different ADC & beta;-lactamase variantswith K (i) values MB076 acted synergistically in combination with multiple cephalosporinsto restore susceptibility. ADC variants containing an alanine duplicationin the & omega;-loop, specifically ADC-33, exhibited increased activityfor larger cephalosporins, such as ceftazidime, cefiderocol, and ceftolozane.X-ray crystal structures of ADC variants in this study provide a structuralcontext for substrate profile differences and show that the inhibitoradopts a similar conformation in all ADC variants, despite small changesnear their active sites.