Targeting Superoxide dismutase confers enhanced Reactive Oxygen Species mediated eradication of Polymyxin B induced Acinetobacter baumannii persisters

• Published in: Antimicrobial agents and chemotherapy Vol. 95; no. 5
• Main Authors: Dubey, Vineet, Gupta, Rinki, Pathania, Ranjana
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 19.04.2021
• Subjects: Experimental Therapeutics; rifampicin; drug tolerance; drug combination; reactive oxygen species; sodB
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02180-20

Bacterial persisters represent non-inheritable drug tolerant population that are linked to recalcitrance of infections in healthcare settings. The rise of antibiotic resistance and depletion of new antibiotics in drug discovery pipeline has made the task of persister eradication more daunting. In the present study, we report that treatment of with the last resort antibiotic polymyxin B displays continuous variation in tolerance among different clinical isolates. Mechanistically, Polymyxin B persisters exhibit disruption of proton motive force led delocalisation of cell division protein to attain a growth arrested phenotype. Tolerance studies on mutant strains revealed that superoxide dismutase ( ) activity is a major contributor in tolerance of to polymyxin B. Using a dual fluorescence based persister detection system, screening of various antibiotics was performed to eradicate polymyxin B induced persisters of Rifampicin exhibited eradication of polymyxin B tolerant population by log reduction of 6 in magnitude against different clinical isolates of We establish that enhanced generation of ROS by rifampicin leads to clearance of these polymyxin B persisters. It was further demonstrated, as a proof of concept, that rifampicin potentiates the killing of polymyxin B persisters in murine wound infection model. We found that the effects were linked to significant down regulation of by rifampicin, which contributes to higher generation of ROS in polymyxin B tolerant cells. In view of these results, we propose that the combination of polymyxin B and rifampicin is an effective antipersister strategy in clearing polymyxin B induced persisters.