Metabolite-enabled eradication of bacterial persisters by aminoglycosides

Abstract

Bacterial persistence is a state in which a sub-population of dormant cells (persisters) tolerates antibiotic treatment1-4. Bacterial persisters have been implicated in biofilms and chronic and recurrent infections5-7. Despite this clinical relevance, there are currently no viable means for eradicating persisters. Here we show that specific metabolic stimuli enable aminoglycoside killing of both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) persisters. This potentiation is aminoglycoside-specific, does not rely on growth resumption, is effective in both aerobic and anaerobic conditions, and proceeds by generation of proton-motive force (PMF) which facilitates aminoglycoside uptake. Our results demonstrate that persisters, though dormant, are primed for metabolite uptake, central metabolism, and respiration. We show that aminoglycosides in combination with specific metabolites can be used to treat E. coli and S. aureus biofilms. Further, we demonstrate that this approach can improve treatment of chronic infection in a mouse urinary tract infection model. This work establishes a metabolic-based strategy for eradicating bacterial persisters and highlights the critical importance of metabolic environment to antibiotic treatment.

Growth on mannitol-rich media elicits a genome-wide transcriptional response in Burkholderia multivorans that impacts on multiple virulence traits in an exopolysaccharide-independent manner

“…In addition to its application as an osmolyte, mannitol and other simple sugars (and their derivatives) are being investigated as antimicrobial therapies. For example, mannitol can potentiate the activity of aminoglycosides, enhancing persister-cell eradication in vitro and the treatment of a chronic murine infection model (Allison et al, 2011). Similarly, mannose (in conjunction with other simple sugars) diminishes lung damage and potentiates standard antibiotic therapy in a murine model of P. aeruginosa pneumonia (Bucior et al, 2013).…”

Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis

“…Despite intensive focus on the primary drug-target interaction and its maladaptive consequences, knowledge of the endogenous mechanisms used by bacteria to resist antibiotic activity is incomplete and centred chiefly around mechanisms associated with the drug-target interaction, such as drug efflux pumps and antibiotic-and/or target-modifying enzymes 3 . However, growing evidence has implicated a broader range of physiologic factors [7][8][9][10]27 .…”

“…More recent studies have begun to revise this view with the demonstration that even non-, or slowly, replicating bacteria could be rendered sensitive to antibiotics. Studies of Escherichia coli, Staphylococcus aureus and even Mtb have shown that the activity of many antibiotics: (i) is dependent on the activity of specific metabolic pathways, (ii) differs for replicating and nonreplicating populations and (iii) can be dissociated from growth rate 7,12,27 . In Mtb, it was shown that adaptation to hypoxia was accompanied by a redirection of metabolic flux away from the TCA cycle and towards the generation of triglycerides, whose inhibition resensitized Mtb to antibiotics in absence of growth 7 .…”

Antibiotics induce redox-related physiological alterations as part of their lethality

“…This notion suggests extrinsic manipulation of bacterial cell metabolism may be exploited to enhance the killing efficacy of existing antibiotics. Indeed, recent work demonstrates that metabolic perturbations (102) or ROS elevation (92) can improve bactericidal lethality.…”