Tea tree oil nanoemulsion targets AgrA protein potentiates amoxicillin efficacy against methicillin-resistant Staphylococcus aureus

The excessive utilization of antibiotics gives rise to the development of bacterial resistance, the deterioration of animal immune functions, the increase in mortality rates, and the undermining of human immunity. Therefore, there is an urgent necessity to explore new antimicrobial agents or alternatives to tackle bacterial resistance. We investigated tea tree oil (TTO), a pure natural plant essential oil extracted from Melaleuca leaves, which exerted efficient antibacterial activities. However, the poor solubility and high volatility of TTO limited the clinical application. Therefore, tea tree oil and Tween 80 were formulated into a stable nanoemulsion (Nano TTO). We attested that Nano TTO, as an antibiotic adjuvant, enhanced the antibacterial activity of amoxicillin (AMX) against methicillin-resistant Staphylococcus aureus (MRSA) and inhibited the formation of biofilms. Mechanistic studies proved that the Nano TTO potentiation effect on AMX was primarily the result of inhibition of the Agr expression by targeting the accessory regulator AgrA. Furthermore, Nano TTO effectively boosts the efficacy of amoxicillin in the mouse septicaemia model and mouse skin wound infection model. Overall, these results revealed the potential of Nano TTO as an adjuvant to evade multidrug-resistant bacterial pathogens and improve treatment outcomes for drug-resistant infections.