Bacterial resistance is becoming increasingly serious, the present study aimed to investigate the mechanism of antibacterial sensitization effect of DHA27 combined with
tobramycin in
tobramycin-resistant Pseudomonas aeruginosa (PA). We found that DHA27 combined with
aminoglycosides had an antibacterial sensitization effect on PA.
Tobramycin, owing to its lower toxic and side effects, was selected to further study the molecular mechanism of
drug combination. A sublethal-dose bacterial challenge/
sepsis mouse model was established to study the protective effect of DHA27 plus
tobramycin. Scanning electron microscopy was used to investigate whether DHA27 exerts the antibacterial sensitization effect by directly affecting bacterial morphology. The effect of DHA27 on
daunorubicin accumulation in bacteria was studied, and quantitative reverse transcription PCR was used to study the effect of DHA27 plus
tobramycin on
16S rRNA methyltransferase and
aminoglycoside-modifying
enzyme mRNA expression. Twenty clinical isolates of PA were found to be
tobramycin resistant; DHA27 plus
tobramycin had a significant antibacterial sensitization effect on many of these resistant strains. DHA27 plus
tobramycin reduced the bacterial load in the spleen and lungs of
sepsis model mice and levels of proinflammatory
cytokines interleukin-1β (IL-1β) and
interferon-γ (IFN-γ). DHA27 plus
tobramycin significantly inhibited the
mRNA expression of
aminoglycoside-modifying
enzymes in bacteria. DHA27 combined with AGs had an antibacterial sensitization effect on PA; the molecular mechanism underlying this effect is closely related to the inhibition of the
mRNA expression of
aminoglycoside-modifying
enzymes, especially aac(3)-II.