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Abstract
Bacterial persister cells are phenotypic variants that exhibit transient antibiotic tolerance and play a leading role in chronic infections and the development of antibiotic resistance. Determining the mechanism that underlies persister formation and developing anti-persister strategies, therefore, are clinically important goals. Here, we report that many gram-negative and gram-positive bacteria become highly tolerant to typical bactericidal antibiotics when the carbon source for their antibiotic-sensitive exponential growth phase is shifted to fumarate, suggesting a role for fumarate in persister induction. Nutrient shift-induced Escherichia coli but not Staphylococcus aureus persister cells can be killed by aminoglycosides upon hypoionic shock (i.e., the absence of ions), which is achieved by suspending the persisters in aminoglycoside-containing pure water for only 1 or 2 min. Such potentiation can be abolished by inhibitors of the electron transport chain (e.g., NaN3) or proton motive force (e.g., CCCP). Additionally, we show that hypoionic shock facilitates the eradication of starvation-induced E. coli but not S. aureus persisters by aminoglycosides, and that such potentiation can be significantly suppressed by NaN3 or CCCP. Mechanistically, hypoionic shock dramatically enhances aminoglycoside uptake by both nutrient shift- and starvation-induced E. coli persisters, whereas CCCP can diminish this uptake. Results of our study illustrate the general role of fumarate in bacterial persistence and may open new avenues for persister eradication and aminoglycoside use.
Highlights
Bacterial persistence is a state in which a sub-population of non-growing/slowly growing bacterial cells resist killing by supralethal concentrations of bactericidal antibiotics (Balaban et al, 2004; Lewis, 2010)
A carbon source shift from glucose to fumarate was recently reported to induce the formation of E. coli persister cells (Kim et al, 2016; Radzikowski et al, 2016)
We examined whether such a nutrient shift from glucose to fumarate could induce persister formation in other bacterial strains, including both gram-negative and gram-positive pathogens, and, if so, whether an aminoglycoside coupled with hypoionic shock could kill those persisters
Summary
Bacterial persistence is a state in which a sub-population of non-growing/slowly growing bacterial cells (i.e., persisters) resist killing by supralethal concentrations of bactericidal antibiotics (Balaban et al, 2004; Lewis, 2010). Amato et al (2013) found that diauxic shifts following exposure to fumarate or succinate can stimulate persister formation in exponentialphase E. coli cells (Amato and Brynildsen, 2014). Various metabolites such as glucose and mannitol may reverse the antibiotic tolerance of stationary-phase persister cells (Allison et al, 2011; Barraud et al, 2013; Meylan et al, 2017). The antibiotic tolerance of bacterial persisters appears to be tightly regulated by cellular respiration (Lobritz et al, 2015; Conlon et al, 2016; Meylan et al, 2017; Shan et al, 2017; Wang et al, 2018; Pu et al, 2019), which may affect both antibiotic uptake and downstream lethal actions of antibiotics (Lobritz et al, 2015; Meylan et al, 2017)
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