13-(2-Methylbenzyl) Berberine Is a More Potent Inhibitor of MexXY-Dependent Aminoglycoside Resistance than Berberine

• Published in: Antibiotics (Basel) Vol. 8; no. 4; p. 212
• Main Authors: Kotani, Kenta, Matsumura, Mio, Morita, Yuji, Tomida, Junko, Kutsuna, Ryo, Nishino, Kunihiko, Yasuike, Shuji, Kawamura, Yoshiaki
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.11.2019; MDPI
• Subjects: Achromobacter; Alzheimer's disease; Amikacin; Aminoglycoside antibiotics; aminoglycoside resistance; Aminoglycosides; Antibacterial agents; Antimicrobial agents; Bactericidal activity; Berberine; Carbenicillin; Care and treatment; Drug resistance; Efflux; Gentamicin; Health aspects; Inhibitors; mexxy; Multidrug resistance; Nosocomial infections; Physiological aspects; Pseudomonas aeruginosa; Pseudomonas aeruginosa infections; Synthesis; Tetracyclines; Time; Japan; Pseudomonas aeruginosa; aminoglycoside resistance; efflux; MexXY; berberine
• ISSN: 2079-6382; 2079-6382
• DOI: 10.3390/antibiotics8040212

We previously showed that berberine attenuates MexXY efflux-dependent aminoglycoside resistance in . 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 strain. Moreover, 13-o-MBB significantly reduced the MICs of gentamicin and amikacin in and . The fractional inhibitory concentration indices indicated that 13-o-MBB acted synergistically with aminoglycosides in only MexXY-positive strains. Time-kill curves showed that 13-o-MBB or higher concentrations of berberine increased the bactericidal activity of gentamicin by inhibiting MexXY in . 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.