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

Abstract

The emergence and spread of multidrug-resistant P. aeruginosa 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 Coptis japonica var. major Satake) or Phellodendri Cortex (the bark of Phellodendron chinense Schneider) markedly reduced resistance to anti-pseudomonal aminoglycosides (e.g., amikacin) in multidrug-resistant P. aeruginosa strains. Berberine, the most abundant benzylisoquinoline alkaloid in the two extracts, reduced aminoglycoside resistance of P. aeruginosa via a mechanism that required the MexXY multidrug efflux system; berberine also reduced aminoglycoside MICs in Achromobacter xylosoxidans and Burkholderia cepacia, 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 P. aeruginosa in the presence of PAβN. Moreover, berberine enhanced the synergistic effects of amikacin and piperacillin (and vice versa) in multidrug-resistant P. aeruginosa strains. Thus, berberine appears to be a novel type inhibitor of the MexXY-dependent aminoglycoside efflux in P. aeruginosa. As aminoglycosides are molecules of choice to treat severe infections the clinical impact is potentially important.

Synergistic Activity of Berberine with Azithromycin against Pseudomonas Aeruginosa Isolated from Patients with Cystic Fibrosis of Lung In Vitro and In Vivo

“…Thus, exploiting novel agents with antimicrobial potentials against PA become urgent. Although BER has been extensively investigated in some bacteria such as Staphylococcus aureus (MIC = 32-256 µg/mL), less studies were focused on the antipseudomonal activity of BER which was relatively weak (MIC ≥ 512 µg/mL) [25, 40]. Our experiments confirmed the poor antipseudomonal activity of BER (MIC > 1024 µg/mL).…”

“…Several reports displayed that both AZM and BER could target efflux pumps (MexXY) [40, 45] and eDNA [26, 30] in PA. However, macrolides were supposed to be difficult of diffusion across the outer membrane of most gram-negative bacteria [46].…”

Antimicrobial Resistance in Pseudomonas aeruginosa: A Concise Review

“…MexX). Resistance nodulation division (RND) involves the MexXY efflux system which develops the resistance in Pseudomonas species [70,71]. MexAB-OprM shows resistance against ticarcillin, broad-spectrum cephalosporin and β-lactam of clinical isolates, while the combination of MexAB-OprM, MexCD-OprJ and MexXY-OprM shows the carbapenem resistance [72].…”

A <i>Pseudomonas aeruginosa</i> Quorum-Sensing autoinducer analog enhances the activity of antibiotics against resistant strains

“…Treatments of infections provoked by antibiotic-resistant bacteria often include cocktails of multiple antimicrobial agents such as β-lactams and fluoroquinolones or aminoglycosides (4)(5)(6). Alternatively, combining antibiotics with efflux pump inhibitors (EPIs) is considered (7)(8)(9).…”