Details

Autor(en) / Beteiligte

• Rosenberg, Christopher R
• Fang, Xin
• Allison, Kyle R
• Beloin, Christophe

Titel

Potentiating aminoglycoside antibiotics to reduce their toxic side effects

Ist Teil von

• PloS one, 2020-09, Vol.15 (9), p.e0237948

Ort / Verlag

San Francisco: Public Library of Science

Erscheinungsjahr

2020

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• The lack of new antibiotics necessitates the improvement of existing ones, many of which are limited by toxic side effects. Aminoglycosides, antibiotics with excellent activity and low bacterial resistance, are hampered by dose-dependent toxic effects in patients (nephrotoxicity, ototoxicity). High antibiotic concentrations are often required to treat dormant, non-dividing bacteria, though previous studies show that aminoglycosides can be activated against such bacteria by specific metabolites. Here, we employed this mechanism to greatly boost the activity of low concentrations of aminoglycosides against prevalent Gram-negative pathogens (Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae), suggesting that less toxic drug concentrations might be used effectively in patients. We go on to show that this effect improved treatment of biofilms, did not increase aminoglycoside resistance, and was due to the generation of proton-motive force (PMF). By single-cell microscopy, we demonstrate that stationary-phase cells, while non-dividing, actively maintain a growth-arrested state that is not reversed by metabolite addition. Surprisingly, within starved populations, we observed rare cells (3%) that divided without added nutrients. Additionally, we discovered that mannitol could directly protect human kidney cells from aminoglycoside cytotoxicity, independent of the metabolite's effect on bacteria. This work forwards a mechanism-based strategy to improve existing antibiotics by mitigating their toxic side effects.