posted on 2021-12-01, 19:03authored byHaoran Chen, Ning Yang, Yi Yang, Yahong Zheng, Mengran Xu, Hui Zhang, Yanyan Liu, Weihua Shen, Jiabin Li
Given the growing rate of Gram-negative
bacterial infections, antibiotics
are now frequently prescribed for various respiratory diseases. Doxofylline
is a newer generation xanthine with both bronchodilating and anti-inflammatory
activities, but its influence on antibiotics remains poorly understood.
Here, we first report the discovery of doxofylline-induced high minimum
inhibitory concentrations of antibiotics. We also showed that doxofylline
blocked antimicrobial-mediated killing for Gram-negative pathogens
in vitro and in murine lung infection models in vivo. By combining
efflux pump inhibition tests, gene expression analyses, and using
the gene tolC knockout strain, we found that doxofylline
positively regulated gene expression of the AcrAB-TolC efflux pump
and attenuated the effect of doxofylline on antibacterial activities
in ΔtolC mutants. Notably, doxofylline-mediated
protection correlated with decreased reactive oxygen species (ROS)
production. Collectively, our study indicates that doxofylline protects
Gram-negative bacteria from antimicrobial lethality by regulating
the AcrAB-TolC efflux pump in a TolC-dependent manner and suppressing
antibiotic-induced ROS accumulation. These results suggest caution
when using antibiotics alongside doxofylline in clinical treatment.