Artificial sweeteners inhibit multidrug‐resistant pathogen growth and potentiate antibiotic activity

Abstract

Antimicrobial resistance is one of the most pressing concerns of our time. The human diet is rich with compounds that alter bacterial gut communities and virulence-associated behaviours, suggesting food additives may be a niche for the discovery of novel anti-virulence compounds. Here, we identify three artificial sweeteners, saccharin, cyclamate and acesulfame-K (ace-K), that have a major growth inhibitory effect on priority pathogens. We further characterise the impact of ace-K on multidrug-resistant Acinetobacter baumannii, demonstrating that it can disable virulence behaviours such as biofilm formation, motility and the ability to acquire exogenous antibiotic-resistant genes. Further analysis revealed the mechanism of growth inhibition is through bulgemediated cell lysis and that cells can be rescued by cation supplementation. Antibiotic sensitivity assays demonstrated that at sublethal concentrations, ace-K can resensitise A. baumannii to last resort antibiotics, including carbapenems. Using a novel ex vivo porcine skin wound model, we show that ace-K antimicrobial activity is maintained in the wound microenvironment. Our findings demonstrate the influence of artificial sweeteners on pathogen behaviour and uncover their therapeutic potential.

The artificial sweetener neotame negatively regulates the intestinal epithelium directly through T1R3-signaling and indirectly through pathogenic changes to model gut bacteria

“…These differences in the literature may be due to the differences in concentration of sweetener studied. For example, de Rios et al studied sweeteners up to 440 μM ( 42 ) and Wang et al investigated concentrations in the 30–80 mM range, which are significantly higher than the concentrations described to be physiological ( 43 ) whereas our studies focused on sweeteners at 100 μM. Hence, the contradictory results from recent research could be explained due to differences in the concentration of the sweeteners used.…”

“…In contrast to the human cells, the different model gut bacteria studied in the present work, E. faecalis, Shigella, E. faecium , and a range of E. coli , pathogenic and non-pathogenic did not show any changes in growth curve in response to neotame exposure at concentrations between 0 and 2 mM. Whilst some studies demonstrate similar outcomes with different bacteria exposed to a range of artificial sweeteners, such as saccharin, aspartame and sucralose ( 23 , 41 ), studies on multi-drug resistant bacteria such as Acinetobacter baumannii and Pseudomonas aeruginosa in the presence of sweeteners such as acesulfame potassium, sucralose and saccharin show significant bactericidal effects ( 42 ). These differences in the literature may be due to the differences in concentration of sweetener studied.…”

Using next generation antimicrobials to target the mechanisms of infection

“…This highlights the potential of repurposing previously approved drugs as NGAs, with numerous examples having already been described of drugs having off target antivirulence effects on bacteria 133 , 170 , 171 . Similar potential has been seen with dietary compounds, with artificial sweeteners for example having been recently shown to limit the pathogenicity of several MDR pathogens when used at sub-inhibitory concentrations 176 . To effectivity stem the tide of MDR pathogens sweeping through our hospitals, it is essential we continue to develop multiple different approaches to tackle these pathogens.…”

Alteration of oral microbial biofilms by sweeteners

“…In addition, the presence of stevioside was also found to inhibit the transformation of C. albicans , which reduces pathogenicity. The artificial sweetener acesulfame-K reduced the expression of genes encoding Bap (biofilm-associated protein) as well as genes encoding Csu pili (related to twitching motility) in Acinetobacter baumannii [ 30 ]. In particular, acesulfame-K decreased the twitching motility of A. baumannii in a dose-dependent manner.…”

“…Although non-nutritive sweeteners cannot be digested to generate energy, they can be potentially toxic to cells following cellular absorption [ 25 ]. Nevertheless, non-nutritive sweeteners have also been shown recently to be beneficial in managing microbial infections [ [26] , [27] , [28] , [29] , [30] ]. Bulk sweeteners also exhibit antibacterial efficacy against a variety of drug-resistant pathogens [ [31] , [32] , [33] ].…”