The emergence and prevalence of methicillin-resistant Staphylococcus aureus(MRSA)severely compromises conventionalβ-lactam antibiotics efficacy and poses an extensive global health challenge.Given the close relations...The emergence and prevalence of methicillin-resistant Staphylococcus aureus(MRSA)severely compromises conventionalβ-lactam antibiotics efficacy and poses an extensive global health challenge.Given the close relationship between docosahexaenoic acid(DHA)and metabolic alterations,this study aimed to reveal the novel function of DHA to potentiateβ-lactam antibiotics activity through a lipid peroxidation mechanism.Additionally,DHA exhibited significant inhibitory effects on the catalytic function ofβ-lactamase through interactions with active residues.Herein,the dual-faceted mechanisms of perturbation of lipid metabolism andβ-lactamase catalytic inhibition achieved the potentiated antibacterial efficacy ofβ-lactam antibiotics in combination with DHA against MRSA.Furthermore,to enhance the pharmacodynamic performance and stability of DHA,amoxicillin and DHA co-loaded nanoemulsions(Amo/DHA-NEs)were prepared via high-energy emulsification.Intriguingly,we found that Amo/DHA-NEs effectively rescued MRSA-induced infections in the murine infection models,as evidenced by the superior bacterial clearance and mitigated inflammation.Collectively,this work reveals a potentially exploitable link between DHA-driven metabolic reprogramming andβ-lactams resistance,and we propose combination therapies of DHA andβ-lactams targeting the emerging threat of MRSA infections.展开更多
基金supported by the National Key Research and Development Program of China(2023YFD1800903)the National Natural Science Foundation of China(U23A20242,U24A20453 and 32172912)the China Postdoctoral Science Foundation(2024M751096,GZB20240268).
文摘The emergence and prevalence of methicillin-resistant Staphylococcus aureus(MRSA)severely compromises conventionalβ-lactam antibiotics efficacy and poses an extensive global health challenge.Given the close relationship between docosahexaenoic acid(DHA)and metabolic alterations,this study aimed to reveal the novel function of DHA to potentiateβ-lactam antibiotics activity through a lipid peroxidation mechanism.Additionally,DHA exhibited significant inhibitory effects on the catalytic function ofβ-lactamase through interactions with active residues.Herein,the dual-faceted mechanisms of perturbation of lipid metabolism andβ-lactamase catalytic inhibition achieved the potentiated antibacterial efficacy ofβ-lactam antibiotics in combination with DHA against MRSA.Furthermore,to enhance the pharmacodynamic performance and stability of DHA,amoxicillin and DHA co-loaded nanoemulsions(Amo/DHA-NEs)were prepared via high-energy emulsification.Intriguingly,we found that Amo/DHA-NEs effectively rescued MRSA-induced infections in the murine infection models,as evidenced by the superior bacterial clearance and mitigated inflammation.Collectively,this work reveals a potentially exploitable link between DHA-driven metabolic reprogramming andβ-lactams resistance,and we propose combination therapies of DHA andβ-lactams targeting the emerging threat of MRSA infections.
