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Abstract
ABSTRACTChronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm, which is subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes. The exact mechanisms affecting the antibiotic susceptibility of biofilms remain unclear, but accumulating evidence suggests that the efficacy of several bactericidal antibiotics is enhanced by stimulation of aerobic respiration of pathogens, while lack of O2 increases their tolerance. In fact, the bactericidal effect of several antibiotics depends on active aerobic metabolism activity and the endogenous formation of reactive O2 radicals (ROS). In this study, we aimed to apply hyperbaric oxygen treatment (HBOT) to sensitize anoxic P. aeruginosa agarose biofilms established to mimic situations with intense O2 consumption by the host response in the cystic fibrosis (CF) lung. Application of HBOT resulted in enhanced bactericidal activity of ciprofloxacin at clinically relevant durations and was accompanied by indications of restored aerobic respiration, involvement of endogenous lethal oxidative stress, and increased bacterial growth. The findings highlight that oxygenation by HBOT improves the bactericidal activity of ciprofloxacin on P. aeruginosa biofilm and suggest that bacterial biofilms are sensitized to antibiotics by supplying hyperbaric O2.
Highlights
Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm, which is subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes
This may be in contrast to the consumption of O2 in the endobronchial secretions of cystic fibrosis (CF) patients, in which the vast majority of O2 is consumed by the polymorphonuclear leukocytes (PMNs) for production of reactive O2 species (ROS) and nitric oxide (NO), whereas only a minute part of O2 is consumed by aerobic respiration [8, 15]
The present study utilized a model in which anoxic P. aeruginosa was embedded in an agarose gel, trapping bacteria as aggregates throughout the gel in order to mimic biofilm infection in vivo [14, 30,31,32]
Summary
Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm, which is subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes. In order to mimic situations in CF lungs where intense O2 consumption by activated PMNs prevents engagement of bacterial aerobic respiration we have grown bacterial biofilm without O2 prior to antibiotic treatment and HBOT. Using this approach, we aimed to examine if absent aerobic respiration may be restored by HBOT for clinically relevant durations, leading to increased bactericidal effect of ciprofloxacin
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