Potent synergistic efficacy of 2-methoxy-1,4-naphthoquinone derived from quinones against drug-resistant bacteria  

作　　者：Lei Xu Yonglin Zhou Deyuan Ou Huaizhi Yang Haihua Feng Huangwei Song Ning Xie Xiaodi Niu Xuming Deng Meiyang Sun Peng Zhang Dejun Liu Jianfeng Wang 

机构地区：[1]State Key Laboratory for Zoonotic Diseases,Key Laboratory for Zoonosis Research,Ministry of Education,College of Veterinary Medicine,Jilin University,Changchun,China [2]Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western China,School of Life Sciences,Ningxia University,Yinchuan,China [3]College of Animal Science of Guizhou University,Guiyang,Guizhou,China [4]National Key Laboratory of Veterinary Public Health and Safety,College of Veterinary Medicine,China Agricultural University,Beijing,China [5]Department of Breast Surgery,Jilin Provincial Cancer Hospital,Changchun,China [6]Department of Thoracic Surgery,The First Hospital of Jilin University,Changchun,China [7]College of Veterinary Medicine,China Agricultural University,Beijing,China [8]College of Veterinary Medicine,Jilin University,Changchun,China

出　　处：《One Health Advances》2024年第1期357-373,共17页全健康进展(英文)

基　　金：supported by the National Natural Science Foundation of China(grant No.U22A20523,32202856,32172912 and 32102723);the Postdoctoral Research Foundation of China(Certificate Number:2023 M731291);Interdisciplinary Integration and Innovation Project of JLU(JLUXKJC2021QZ04);the Graduate Innovation Fund of Jilin University(No.2022001).

摘　　要：The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat.Herein,versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance.2-methoxy-1,4-naphthoquinone(MNQ)exhib-ited the potent potentiation(4 to 32-fold)with tetracyclines,along with effective inhibition on biofilm formation.Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4)proteins through interaction with their active residues.Furthermore,exposure to MNQ significantly dissipate the proton motive force,leading to a cascade of membrane structural damage and metabolic homeostasis imbalance.Encouragingly,the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models,as evidenced by the reduced bacterial burden and mitigated pathological injury.Our find-ings propose a potential therapeutic option and a novel tetracyclines’adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).

关 键 词：MNQ Tetracycline adjuvant Tet(X3)/tet(X4) Bacterial metabolism 

分 类 号：R54[医药卫生—心血管疾病]