Can a spoonful of sugar help in the treatment of persistent infections?

A recent article published in the journal Nature suggests that taking antibiotics with certain sugars can improve their effectiveness against persistent infections. As per Allison et al. (2011), bacterial persisters in biofilms can be eradicated by facilitating aminoglycoside uptake when used in combination with specific metabolites. They found that 10 mM glucose, fructose, mannitol and 20 mM pyruvate given along with gentamicin could reduce the number of persisters in vitro by more than 99.9% than with gentamicin alone. This activity was found to be antibiotic specific (i.e. only with aminoglycosides, but not with other groups of antibiotics). The authors found that the metabolites induced an elevated proton motive force in persisters which facilitated the uptake of aminoglycosides resulting in their rapid killing. Since persisters are dormant bacteria with reduced PMF, they usually overcome the bactericidal activity of aminoglycosides by not taking up the antibiotic.

However, if 10mM glucose along with gentamicin can significantly reduce the number of persisters, why should infections persist in our body? The average blood glucose levels in humans fluctuate around 5mM and can go as high as 8-12 mM after a rich meal. Even at 5mM glucose, a significant number of persisters are killed (suppl. Fig. 6a, Allison et al. (2011)). It means that the normal glucose level is high enough to eradicate persisters in biofilms when aminoglycosides are used for treatment.

However, blood glucose levels can vary in different tissues or fluids. For example, glucose concentration is very low in airway secretions of healthy, normal individuals (Philips et al. 2003, Baker et al.2007). Hence it can be argued that addition of sugars with aminoglycosides can work well in chronic infections like cystic fibrosis (CF) or tuberculosis. However, glucose concentrations in nasal or bronchial secretions are usually elevated in hyperglycemia and in inflammatory conditions of lungs including CF (Baker et al. 2007). Equally important is that elevated bronchial glucose is associated with increased respiratory infections (Baker et al. 2007). Thus, in CF and tuberculosis, even though the glucose level in respiratory fluids may be high enough for ‘waking up’ persisters from dormancy, the infection persists.

Similarly, suppl. Fig. 6 (Allison et al. 2011) shows that the eradication of persisters is dependent on metabolite concentration. Does it mean that a patient with diabetes mellitus have greater chance for successful treatment of biofilm related infections with aminoglycosides, as their blood glucose level is higher? As indicated above, respiratory fluid glucose concentration is elevated in hyperglycemic conditions.

However, mannitol given in combination with aminoglycosides can be effective in reducing bacterial load in infections such as CF. But this may not be due to metabolite-enabled elimination of persisters. This aspect will be discussed next.

Allison et al. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473: 216-220.

Baker et al. (2007). Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis. J Appl Physiol 102: 1969-1975.

Philips et al. (2003). Factors determining the appearance of glucose in upper and lower respiratory tract secretions. Intensive Care Med 29:2204-2210