Antibiotic combinations have been previously shown to be highly species-specific (Brochado et al. Nature, 2018). While a mechanistic basis for such specificity is yet to be understood, the potential to use combinations for narrow-spectra treatment, where the pathogen is primarily targeted and the commensal bacterial population is protected, is there. Here we investigate species-specific synergistic combinations against Pseudomonas aeruginosa, a particularly problematic Gram-negative pathogen, given its intrinsic resistance to major classes of antibiotics. Here we focus on understanding the mechanism of action underlying synergy between aminoglycosides and β-lactams, because of it clinical relevance – it is used to treat infections by several Gram-negative pathogens.

We started by assessing synergy across different bacterial strains beyond P. aeruginosa, including Escherichia coli, Salmonella Typhimurium, Klebsiella pneumoniae, Acinetobacter baumannii, Burkholderia pseudomallei. Our data shows that synergy potency widely varies across all species. It is particularly potent against P. aeruginosa, while the weakest effect is observed for E. coli strains.

Plotz and Davis (Science, 1962) previously showed that Escherichia coli pre-treatment with the β-lactam penicillin, quicken the subsequent killing by the aminoglycoside streptomycin, due to increased uptake. However, it is not understood why the activity of the combination is stronger against P. aeruginosa. In trying to understand the reasons for such species specificity, we next evaluated the activity of the individual antibiotics against E.coli and P.aeruginosa in relation to growth inhibition, killing kinetics and morphology changes. While aminoglycoside activity is very similar between the two species, greater differences can be observed on the β-lactam side, thus suggesting that β-lactam activity is determinant for the synergy. We are currently investigating how beta-lactam specificity impacts synergy outcome. This study will help understanding and improving antibiotic action against P. aeruginosa, one of the most-difficult-to-treat bacterial pathogens of today.