2. Academic Validation
  3. Natural isoflavone biochanin A as a template for the design of new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium

Natural isoflavone biochanin A as a template for the design of new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium

  • Eur J Med Chem. 2017 Nov 10:140:321-330. doi: 10.1016/j.ejmech.2017.09.014.
Rolando Cannalire 1,  Diana Machado 2,  Tommaso Felicetti 1,  Sofia Santos Costa 2,  Serena Massari 1,  Giuseppe Manfroni 1,  Maria Letizia Barreca 1,  Oriana Tabarrini 1,  Isabel Couto 2,  Miguel Viveiros 2,  Stefano Sabatini 3,  Violetta Cecchetti 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, 06123 Perugia, Italy.
  • 2 Unidade de Microbiologia Médica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal.
  • 3 Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, 06123 Perugia, Italy. Electronic address: stefano.sabatini@unipg.it.
PMID: 28964936 DOI: 10.1016/j.ejmech.2017.09.014
Abstract

Mycobacterium avium is a difficult-to-treat pathogen able to quickly develop drug resistance. Like for Other microbial species, overexpression of efflux pumps is one of the main mechanisms in developing multidrug resistance. Although the use of efflux pumps inhibitors (EPIs) represents a promising strategy to reverse resistance, to date few M. avium EPIs are known. Recently, we showed that in-house 2-phenylquinoline S. aureus NorA EPIs exhibited also a good activity against M. avium efflux pumps. Herein, we report a series of 3-phenylquinolones designed by modifying the isoflavone biochanin A, a natural EPI of the related M. smegmatis, taking into account some important SAR information obtained around the 2-phenylquinoline NorA EPIs. The 3-phenylquinolones inhibited M. avium efflux pumps with derivatives 1e and 1g that displayed the highest synergistic activity against all the strains considered in the study, bringing down (from 4- to 128-fold reduction) the MIC values of macrolides and fluoroquinolones.

Keywords

3-Phenylquinolones; Antimicrobial resistance; Efflux pump inhibitors; M. avium complex; Nontuberculous mycobacteria.

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