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Antibiotic resistance/tolerance has become a severe threat to human and animal health. To combat antibiotic-resistant/tolerant bacteria, it is of significance to improve the efficacy of traditional antibiotics. Here we show that indole potentiates tobramycin to kill stationary-phase  Staphylococcus aureus  cells after a short, combined treatment, with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite. Consistently, this combined treatment also kills various types of  S. aureus  persister cells as induced by the protonophore CCCP, nutrient shift, or starvation, as well as methicillin-resistant  S. aureus  (MRSA) cells. Importantly, 5-methylindole potentiates tobramycin killing of  S. aureus  persisters in a mouse acute skin wound model. Furthermore, 5-methylindole facilitates killing of many strains of gram-positive pathogens such as  Staphylococcus epidermidis, Enterococcus faecalis , and  Streptococcus pyogenes  by aminoglycoside antibiotics, whereas it suppresses the action of aminoglycoside against the gram-negative pathogens  Escherichia coli  and  Shigella flexneri . In conclusion, our work may pave the way for the development of indole derivatives as adjuvants to potentiate aminoglycosides against gram-positive pathogens.

5-Methylindole Potentiates Aminoglycoside Against Gram-Positive Bacteria Including Staphylococcus aureus Persisters Under Hypoionic Conditions