Abstract
Persisters are phenotypic variants of normal susceptible bacterial populations that survive prolonged exposure to high doses of antibiotics and are responsible for pertinacious infections and post-treatment relapses. Out of the three antibiotics, Acinetobacter baumannii formed the highest percentage of persister cells against rifampicin followed by amikacin and the least against colistin. Colistin-treated cells formed the high levels of reactive oxygen species (ROS) whose quenching with bipyridyl and thiourea led to an increased persister population. Curcumin, a polyphenolic pro-oxidant, significantly decreased persistence against colistin. The quenching of ROS generated by curcumin-colistin combination and the use of resveratrol, an anti-oxidant, with colistin increased the persister population, supporting the significance of ROS in decreased persistence against this combination. The down-regulation of repair genes by this combination in comparison to colistin alone supported the modulation of gene expression in response to ROS and their importance in decreased persistence. Increased membrane permeability by colistin, facilitating the penetration of curcumin into cells and resulting in increased ROS and compromised repair compounded by the decreased efflux of colistin by the inhibition of efflux pumps, may be responsible for enhanced lethality and low persistence. Hence, the curcumin-colistin combination can be another option with anti-persister potential for the control of chronic A. baumannii infections.
Highlights
Acinetobacter baumannii is a Gram-negative, aerobic pathogen, responsible for nosocomial infections worldwide, including hospital-acquired pneumonia and bloodstream, urinary tract, skin and soft tissue infections[1]
The time-dependent assay revealed maximum persisters (1.92%) against rifampicin at 20X MIC, 0.10% against amikacin at 40X MIC and the lowest level (0.08%) against colistin (10X MIC) at 24 h; this was revealed by the typical biphasic killing with a sharp decline in the susceptible cells followed by a plateau of the surviving persister subpopulation (Fig. 1)
This study has demonstrated that A. baumannii forms varying levels of persister cells, which are lowest with colistin, higher with amikacin and the highest with rifampicin
Summary
Acinetobacter baumannii is a Gram-negative, aerobic pathogen, responsible for nosocomial infections worldwide, including hospital-acquired pneumonia and bloodstream, urinary tract, skin and soft tissue infections[1]. Apart from multi-drug resistance, A. baumannii exhibits multidrug tolerance mediated by persister cells that are responsible for chronic infections[5,6]. It is reported to act in synergism with various antibiotics against Gram-positive and Gram-negative bacteria[18,19,20,21] This is the first study to investigate the anti-persister potential of curcumin in combination with antibiotics, which could be explored as an option to manage recurrent and chronic A. baumannii infections. The curcumin-colistin combination was most effective in reducing persistence, which could be due to the increased ROS production and efflux pump inhibition by curcumin aided by the increased membrane permeability by colistin
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