Synergistic activity of menadione in combination with colistin against colistin-susceptible and colistin-resistant Gram-negative bacteria.

Objective: Antibiotic resistance poses a formidable challenge, especially with the emergence of multidrug-resistant Gram-negative bacteria. Colistin serves as a last-resort antibiotic to combat multidrug-resistance, but it is limited by its nephrotoxicity and rising resistance. This study introduces menadione, a synthetic form of vitamin K, as a potential adjuvant to enhance colistin's efficacy against both susceptible and resistant strains of Gram-negative bacteria.

Methods: Through checkerboard dilution assays, we demonstrate that menadione significantly lowers the MICs of colistin, with fractional inhibitory concentration indices ranging from 0.031 to 0.375. Furthermore, synergistic effects were confirmed via time-kill kinetics, indicating effective bacterial growth inhibition. The study also explores the mechanism underlying this synergy, revealing that menadione in combination with colistin disrupts the bacterial outer membrane, reduces the proton motive force and adenosine triphosphate content, and amplify the production of reactive oxygen species, contributing to bacterial cell death.

Results: Menadione was shown to prevent the evolution of colistin resistance.

Conclusions: This research highlights the potential of using menadione as a colistin adjuvant to combat antibiotic-resistant Gram-negative bacteria, providing a promising approach to extend the utility of existing antibiotics in clinical settings.