Exogenous Alanine and/or Glucose plus Kanamycin Kills Antibiotic-Resistant Bacteria

Abstract

Multidrug-resistant bacteria are an increasingly serious threat to human and animal health. However, novel drugs that can manage infections by multidrug-resistant bacteria have proved elusive. Here we show that glucose and alanine abundances are greatly suppressed in kanamycin-resistant Edwardsiella tarda by GC-MS-based metabolomics. Exogenous alanine or glucose restores susceptibility of multidrug-resistant E. tarda to killing by kanamycin, demonstrating an approach to killing multidrug-resistant bacteria. The mechanism underlying this approach is that exogenous glucose or alanine promotes the TCA cycle by substrate activation, which in turn increases production of NADH and proton motive force and stimulates uptake of antibiotic. Similar results are obtained with other Gram-negative bacteria (Vibrio parahaemolyticus, Klebsiella pneumoniae, Pseudomonas aeruginosa) and Gram-positive bacterium (Staphylococcus aureus), and the results are also reproduced in a mouse model for urinary tract infection. This study establishes a functional metabolomics-based strategy to manage infection by antibiotic-resistant bacteria.

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis

“…For example, Lobritz et al (2015) demonstrated a link between cellular respiration in Escherichia coli and Staphylococcus aureus and antibiotic efficacy. Peng et al (2015) showed that promoting TCA flux to increase NADH and consequently proton motive force in multidrug-resistant Edwardsiella tarda restored susceptibility to kanamycin. In the case of Mtb , metabolic profiling revealed that exposure to sub-lethal concentrations INH, RIF and streptomycin remodeled Mtb central carbon metabolism to enable antibiotic tolerance (Nandakumar et al, 2014).…”

Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution

“…In contrast, specific metabolites, including several sugars and pyruvate, were shown to enhance the killing efficiency of aminoglycoside antibiotics against persister bacteria [68 ] -a subpopulation of cells that has phenotypically switched into a dormant state and is notoriously hard to eradicate [69][70][71]. Similarly, the addition of metabolites like glucose and alanine restores the ability of the aminoglycoside kanamycin to kill otherwise antibiotic-resistant bacteria by increasing the proton motive force (PMF) which stimulates aminoglycoside uptake [72] (Figure 3). The interactions between antibiotics and metabolites identified so far are certainly only the tip of the iceberg, highlighting the need to explore such interactions more systematically.…”

“…(a) Schematic illustrating how the PMF is generated by the electron transport chain in aerobic conditions: protons (H + ) are moved from the cytoplasm to the periplasm. Stimulating this process by adding glucose or other metabolites can restore aminoglycoside susceptibility in persisters [68 ] and in aminoglycoside-resistant bacteria [72]. (b) The uptake of aminoglycosides depends on the PMF: the free energy released by moving protons from the periplasm to the cytoplasm is used for aminoglycoside uptake.…”

Metabolome strategy against Edwardsiella tarda infection through glucose-enhanced metabolic modulation in tilapias

“…Using this approach, we show that interferon-a2b promotes biosynthesis of unsaturated fatty acids, which in turn plays a role in eliminating bacterial pathogens [14]; N-acetylglucosamine elevates metabolic defense ability of tilapias infected by Streptococcus iniae cultured at 22 C [15]; L-proline increases survival of tilapias infected by Streptococcus agalactiae in higher water temperature [16]. We also show that alanine, glucose or fructose revert antibiotic-resistant metabolome to antibiotic-susceptible metabolome and potentiate antibiotics to kill multidrug-resistant bacteria [17,18]. These results indicate that complement of crucial metabolites identified from a metabolic strategy can become an alternative way to cope with the microbial infections.…”