Abstract
Bacterial persistence is a feature that allows susceptible bacteria to survive extreme concentrations of antibiotics and it has been verified in a number of species, such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus spp., Mycobacterium spp. However, even though Acinetobacter baumannii is an important nosocomial pathogen, data regarding its persistence phenotype are still lacking. Therefore, the aim of this study was to evaluate the persistence phenotype in A. baumannii strains, as well as its variation among strains after treatment with polymyxin B and tobramycin. Stationary cultures of 37 polymyxin B-susceptible clinical strains of A. baumannii were analyzed for surviving cells after exposure to 15 µg/mL of polymyxin B for 6 h, by serial dilutions and colony counting. Among these, the 30 tobramycin-susceptible isolates also underwent tobramycin treatment at a concentration of 160 µg/mL and persister cells occurrence was evaluated equally. A high heterogeneity of persister cells formation patterns among isolates was observed. Polymyxin B-treated cultures presented persister cells corresponding from 0.0007% to 10.1% of the initial population and two isolates failed to produce detectable persister cells under this condition. A high variability could also be observed when cells were treated with tobramycin: the persister fraction corresponded to 0.0003%–11.84% of the pre-treatment population. Moreover, no correlation was found between persister subpopulations comparing both antibiotics among isolates, indicating that different mechanisms underlie the internal control of this phenotype. This is the first report of persister cells occurrence in A. baumannii. Our data suggest that distinct factors regulate the tolerance for unrelated antibiotics in this species, contrasting the multi-drug tolerance observed in other species (eg. dormancy-mediated tolerance). Supporting this observation, polymyxin B – an antibiotic that is believed to act on non-dividing cells as well – failed to eradicate persister cells in the majority of the isolates, possibly reflecting a disconnection between persistence and dormancy.
Highlights
Acinetobacter baumannii is a nosocomial pathogen responsible for numerous deaths
The susceptibility to tobramycin and polymyxin B were previously evaluated by disk diffusion method and microdilution, respectively, according to the Clinical and Laboratory Standards Institute’s (CLSI) recommendations [16]
All clinical strains tested were susceptible to polymyxin B, presenting Minimum Inhibitory Concentration (MIC) values ranging from 0.5 to 2 mg/mL
Summary
Much has been elucidated about its resistance phenotype and mechanisms, very little is known about the persistence phenotype in this species. Mathematical models suggest that an interaction of multiple toxin-antitoxin (TA) systems together may regulate the presence and intensity of this tolerance phenotype [14]. Supporting this idea, some TA systems have been found to impact significantly in the composition and quantity of the antibiotic-tolerant subpopulation of a susceptible strain [7,13,15]. The ability to form persister cells has not yet been reported in A. baumannii, even though it is a major nosocomial pathogen that is often unresponsive to treatment. The aim of this study was to verify the persistence phenotype in A. baumannii strains, as well as the variation of this phenotype among strains following antimicrobial exposure
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