本项目基于申请人新近在Cell Metabolism有关丙氨酸、葡萄糖和果糖促进三羧酸循环、提高质子动力势(PMF)、增加抗生素摄取，促进抗生素杀菌的新发现，以及前期有关ATP促进卡那霉素摄取和杀菌的研究结果，拟进一步深入研究PMF逆转耐药性的下游ATP的分子机制。重点阐明ATP促进抗生素杀菌的作用机制，揭示ATP代谢途径在促进杀菌中的意义，发现ATP合酶在提高细菌对抗生素敏感性的调节作用，这对全面而深入地发现丙氨酸、葡萄糖和果糖逆转耐药性的分子机理、促进其应用具有十分重要的价值；同时鉴于既往仅知PMF可以促进氨基糖苷类抗生素的摄取，但具体机制尚不清楚，这一分子机制的阐明将积极推进对PMF促进氨基糖苷类抗生素机制的深入认识。进一步对于筛选药物作用新靶点，建立新的治疗策略，促进健康养殖、保证食品安全也具有十分重要的意义。

This proposal is to perform a thorough investigation of the molecular mechanism of how ATP promotes kanamycin uptake and eradicate antibiotic-resistant bacteria. As we previously showed that exogenous alanine, glucose and fructose would promote TCA cycle, generate more proton motive force, elevate antibiotic uptake, and thereby improve antibiotic efficacy in combating with antibiotic-resistant bacteria, which was published in Cell Metabolism early last year. Our preliminary data showed that ATP, the downstream product of proton motive force, has similar effect as alanine and glucose, but the mechanism is unknown. Therefore, in this proposal, we have three specific aims including the mechanism of ATP-facilitated antibiotic killing of bacteria, the role ATP metabolism in antibiotic resistance, and the function of ATP synthase in antibiotic-resistance. By this way, we would expand the understanding the mechanism of alanine, glucose and fructose facilitated antibiotic killing. Moreover, the mechanism of how PMF promote the uptake of aminoglycosides is also a puzzle. The results derived from this proposal will pave the way for target drug design, novel treatment strategy, green farming, and food safety.