Targeting Superoxide Dismutase Confers Enhanced Reactive Oxygen Species-Mediated Eradication of Polymyxin B-Induced Acinetobacter baumannii Persisters

Abstract

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 Acinetobacter baumannii 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 (sodB) activity is a major contributor in tolerance of A. baumannii to polymyxin B. Using a dual fluorescence based persister detection system, screening of various antibiotics was performed to eradicate polymyxin B induced persisters of A. baumannii. Rifampicin exhibited eradication of polymyxin B tolerant population by log reduction of 6 in magnitude against different clinical isolates of A. baumannii. 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 sodB 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 A. baumannii persisters.

Polymyxin B, Cefoperazone Sodium-Sulbactam Sodium, and Tigecycline against Multidrug-Resistant Acinetobacter baumannii Pneumonia

“…A. baumannii has a variety of drug resistance mechanisms, including beta-lactamase, efferent pump activation and overexpression, membrane permeability reduction, change of penicillin binding protein, and enzymatic modification of aminoglycosides. The main mechanism of drug resistance to hydrocarbapenes is hydrocarbapenase production [ 6 ].…”

Neutrophil-mediated delivery of the combination of colistin and azithromycin for the treatment of bacterial infection

“…Consistent with the previous report, we found that the combination of colistin with azithromycin resulted in superior ll OPEN ACCESS iScience Article bactericidal effects to those of the individual drugs. It has been demonstrated that ROS facilitates the killing of bacteria by antibiotics and elimination of bacterial persister cells (Dubey et al, 2021). Upon encountering bacteria, neutrophils promptly generate ROS (Zeng et al, 2019).…”

The antihelminth drug rafoxanide reverses chromosomal-mediated colistin-resistance in Klebsiella pneumoniae

“…An aliquot of 1 mL of bacterial suspension containing the indicated concentration of rafoxanide or colistin alone or in combination or 100 µM CCCP per se . Incubation for 1 h, then the fluorescence was monitored at excitation/emission of 525/600 nm at 37°C with a luminometer (Varioskan Flash; Thermo Scientific) ( 16 ).…”