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

• Main Authors: Kenta Kotani (Author), Mio Matsumura (Author), Yuji Morita (Author), Junko Tomida (Author), Ryo Kutsuna (Author), Kunihiko Nishino (Author), Shuji Yasuike (Author), Yoshiaki Kawamura (Author)
• Format: Book
• Published: MDPI AG, 2019-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2079-6382; 10.3390/antibiotics8040212
• Keywords: <i>pseudomonas aeruginosa</i>; efflux; mexxy; aminoglycoside resistance; berberine; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 8, Iss 4, p 212 (2019)

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