Abstract
We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in Pseudomonas aeruginosa. Here, we aimed to synthesize berberine derivatives with higher MexXY inhibitory activities. We synthesized 11 berberine derivatives, of which 13-(2-methylbenzyl) berberine (13-o-MBB) but not its regiomers showed the most promising MexXY inhibitory activity. 13-o-MBB reduced the minimum inhibitory concentrations (MICs) of various aminoglycosides 4- to 128 fold for a highly multidrug resistant P. aeruginosa strain. Moreover, 13-o-MBB significantly reduced the MICs of gentamicin and amikacin in Achromobacter xylosoxidans and Burkholderia cepacia. The fractional inhibitory concentration indices indicated that 13-o-MBB acted synergistically with aminoglycosides in only MexXY-positive P. aeruginosa strains. Time-kill curves showed that 13-o-MBB or higher concentrations of berberine increased the bactericidal activity of gentamicin by inhibiting MexXY in P. aeruginosa. Our findings indicate that 13-o-MBB inhibits MexXY-dependent aminoglycoside drug resistance more strongly than berberine and that 13-o-MBB is a useful inhibitor of aminoglycoside drug resistance due to MexXY.
Highlights
Pseudomonas aeruginosa is a major cause of nosocomial infections
Our findings indicate that 13-o-MBB inhibits MexXY-dependent aminoglycoside drug resistance more strongly than berberine and that 13-o-MBB is a useful inhibitor of aminoglycoside drug resistance due to MexXY
We previously reported that berberine attenuates MexXY-dependent aminoglycoside resistance in resistance in[15], P. aeruginosa with athat recent report has thathigh berberine has affinity to a aeruginosa consistent[15], withconsistent a recent report berberine affinity tohigh a MexXY
Summary
Pseudomonas aeruginosa is a major cause of nosocomial infections. Treatment of P. aeruginosa infections with antimicrobial concentrations insufficient to inhibit P. aeruginosa growth results in the emergence of new multidrug resistant P. aeruginosa strains [1] that are difficult to eradicate and may increase mortality [2].Drug efflux is a major mechanism leading to antimicrobial resistance in P. aeruginosa [3].Four resistance-nodulation-division (RND)-type multidrug efflux pumps (MexAB-OprM [4], MexCD-OprJ [5], MexEF-OprN [6] and MexXY-OprM/OprA [7,8]) have been reported as drug efflux systems involved in the drug resistance of P. aeruginosa. Pseudomonas aeruginosa is a major cause of nosocomial infections. Treatment of P. aeruginosa infections with antimicrobial concentrations insufficient to inhibit P. aeruginosa growth results in the emergence of new multidrug resistant P. aeruginosa strains [1] that are difficult to eradicate and may increase mortality [2]. Drug efflux is a major mechanism leading to antimicrobial resistance in P. aeruginosa [3]. Four resistance-nodulation-division (RND)-type multidrug efflux pumps (MexAB-OprM [4], MexCD-OprJ [5], MexEF-OprN [6] and MexXY-OprM/OprA [7,8]) have been reported as drug efflux systems involved in the drug resistance of P. aeruginosa. Only MexXY contributes to aminoglycoside drug resistance [8,9].
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