AUTHOR=Morita Yuji , Nakashima Ken-ichi , Nishino Kunihiko , Kotani Kenta , Tomida Junko , Inoue Makoto , Kawamura Yoshiaki 

TITLE=Berberine Is a Novel Type Efflux Inhibitor Which Attenuates the MexXY-Mediated Aminoglycoside Resistance in Pseudomonas aeruginosa

JOURNAL=Frontiers in Microbiology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2016.01223

DOI=10.3389/fmicb.2016.01223

ISSN=1664-302X

ABSTRACT=<p>The emergence and spread of multidrug-resistant <italic>P. aeruginosa</italic> infections is of great concern, as very few agents are effective against strains of this species. Methanolic extracts from the Coptidis Rhizoma (the rhizomes of <italic>Coptis japonica</italic> var. <italic>major Satake</italic>) or Phellodendri Cortex (the bark of <italic>Phellodendron chinense</italic> Schneider) markedly reduced resistance to anti-pseudomonal aminoglycosides (e.g., amikacin) in multidrug-resistant <italic>P. aeruginosa</italic> strains. Berberine, the most abundant benzylisoquinoline alkaloid in the two extracts, reduced aminoglycoside resistance of <italic>P. aeruginosa</italic> via a mechanism that required the MexXY multidrug efflux system; berberine also reduced aminoglycoside MICs in <italic>Achromobacter xylosoxidans</italic> and <italic>Burkholderia cepacia</italic>, two species that harbor intrinsic multidrug efflux systems very similar to the MexXY. Furthermore this compound inhibited MexXY-dependent antibiotic resistance of other classes including cephalosporins (cefepime), macrolides (erythromycin), and lincosamides (lincomycin) demonstrated using a pseudomonad lacking the four other major Mex pumps. Although phenylalanine-arginine beta-naphthylamide (PAβN), a well-known efflux inhibitor, antagonized aminoglycoside in a MexXY-dependent manner, a lower concentration of berberine was sufficient to reduce amikacin resistance of <italic>P. aeruginosa</italic> in the presence of PAβN. Moreover, berberine enhanced the synergistic effects of amikacin and piperacillin (and vice versa) in multidrug-resistant <italic>P. aeruginosa</italic> strains. Thus, berberine appears to be a novel type inhibitor of the MexXY-dependent aminoglycoside efflux in <italic>P. aeruginosa</italic>. As aminoglycosides are molecules of choice to treat severe infections the clinical impact is potentially important.</p>