Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux

Therapeutic
interventions to treat multidrug-resistant (MDR) Pseudomonas
aeruginosa infections are severely limited
and often require the use of colistin as drug of last resort. The
major challenges impeding the development of novel antipseudomonal
agents are the lack of cell penetration and extensive efflux. We have
discovered a tobramycin–moxifloxacin hybrid core structure
which enhances outer membrane permeability and reduces efflux by dissipating
the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects
of MDR P. aeruginosa. Attempts to select
for resistance over a period of 25 days resulted in a 2-fold increase
in the minimal inhibitory concentration (MIC) for the hybrid, while
moxifloxacin or tobramycin resulted in a 16- and 512-fold increase
in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized
when used in combination with other classes of antibiotics.