CpxA/R-Controlled Nitroreductase Expression as Target for Combinatorial Therapy against Uropathogens by Promoting...

Area of Science:

• Microbiology
• Pharmacology
• Infectious Diseases

Background:

• Antibiotic resistance in uropathogens causes treatment failures and recurrent urinary tract infections (UTIs).
• Novel therapeutic strategies are needed to combat UTIs effectively.

Purpose of the Study:

• To investigate the synergistic effect of amikacin and nitrofurantoin against Gram-negative uropathogens.
• To elucidate the underlying mechanism of this synergistic antimicrobial activity.

Main Methods:

• In vitro and in vivo studies were conducted to assess the efficacy of the drug combination.
• Mechanistic analysis involved studying bacterial envelope stress, Cpx signaling, and nitroreductase expression.

Main Results:

• Amikacin induced bacterial envelope stress, activating the Cpx signaling pathway.
• Activated Cpx signaling upregulated nitroreductase expression (nfsA/nfsB), enhancing nitrofurantoin activation.
• The combination disrupted bacterial redox balance, leading to pathogen clearance via reactive oxygen species (ROS).

Conclusions:

• The amikacin-nitrofurantoin combination shows potential for treating recurrent Gram-negative uropathogen infections.
• Cpx signaling-controlled nitroreductase is a viable target for modulating antibiotic susceptibility.