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Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors

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Abstract

β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of ~1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K i value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.

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Acknowledgments

We kindly acknowledge Prof. Brian K. Shoichet for the availability to test our compounds. GC acknowledges Grant IG15420 from AIRC. We acknowledge the CINECA and the Regione Lombardia award under the LISA initiative, for the availability of high performance computing resources and support.

Author information

Author notes

  1. Jacopo Sgrignani

    Present address: Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland

Authors and Affiliations

  1. ICRM-CNR, Via Mario Bianco 9, 20131, Milan, Italy

    Jacopo Sgrignani & Giorgio Colombo

  2. Dipartimento di Biotecnologie Mediche, Università di Siena, Policlinico “Le Scotte”, Viale Bracci 16, 53100, Siena, Italy

    Filomena De Luca & Jean-Denis Docquier

  3. Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth Street, Byers Hall, San Francisco, CA, 94158, USA

    Hayarpi Torosyan & Da Duan

  4. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milan, Italy

    Beatrice Novati & Giovanni Grazioso

  5. Dipartimento di Scienze della Vita, Università di Modena e Reggio Emilia, Via G. Campi 103, 41125, Modena, Italy

    Fabio Prati

Authors
  1. Jacopo Sgrignani
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  2. Filomena De Luca
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Corresponding authors

Correspondence to Giorgio Colombo or Giovanni Grazioso.

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Sgrignani, J., De Luca, F., Torosyan, H. et al. Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors. J Comput Aided Mol Des 30, 851–861 (2016). https://doi.org/10.1007/s10822-016-9962-8

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  • DOI: https://doi.org/10.1007/s10822-016-9962-8

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