Amphiphilic Tobramycin–Lysine Conjugates Sensitize Multidrug Resistant Gram-Negative Bacteria to Rifampicin and Minocycline

Chromosomally
encoded low membrane permeability and highly efficient
efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that
amphiphilic tobramycin–fluoroquinolone hybrids can enhance
efficacy of fluoroquinolone antibiotics against multidrug-resistant
(MDR) P. aeruginosa isolates. Herein, we report on
a novel class of tobramycin–lysine conjugates containing an
optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative
bacteria to legacy antibiotics. Combination studies indicate the ability
of these conjugates to synergize rifampicin and minocycline against
MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection
model. Mode of action studies indicate that the amphiphilic tobramycin–lysine
adjuvants enhance outer membrane cell penetration and affect the proton
motive force, which energizes efflux pumps. Overall, this study provides
a strategy for generating effective antibiotic adjuvants that overcome
resistance of rifampicin and minocycline in MDR and XDR Gram-negative
bacteria including P. aeruginosa.