biostudies-literatureAntonoplis ANational Cancer InstituteNCI NIH HHSNational Medical Research CouncilNational Institute of General Medical SciencesNIGMS NIH HHSNational Science Foundation16140-16151https://www.ebi.ac.uk/biostudies/studies/S-EPMC6430714biostudies-literatureUnknown140(47)New strategies are urgently needed to target MRSA, a major global health problem and the leading cause of mortality from antibiotic-resistant infections in many countries. Here, we report a general approach to this problem exemplified by the design and synthesis of a vancomycin-d-octaarginine conjugate (V-r8) and investigation of its efficacy in addressing antibiotic-insensitive bacterial populations. V-r8 eradicated MRSA biofilm and persister cells in vitro, outperforming vancomycin by orders of magnitude. It also eliminated 97% of biofilm-associated MRSA in a murine wound infection model and displayed no acute dermal toxicity. This new dual-function conjugate displays enhanced cellular accumulation and membrane perturbation as compared to vancomycin. Based on its rapid and potent activitJournal of the American Chemical SocietyA Dual-Function Antibiotic-Transporter Conjugate Exhibits Superior Activity in Sterilizing MRSA Biofilms and Killing Persister Cells.PMC6430714R01 CA031845CA031845NMRC/CBRG/0086/2015R01 GM117278R37 CA031845Co JYAmieva MRLee YBHuttner MAKline KAZang XChong KKLCegelski LAntonoplis AWender PAfalseA Dual-Function Antibiotic-Transporter Conjugate Exhibits Superior Activity in Sterilizing MRSA Biofilms and Killing Persister Cells.New strategies are urgently needed to target MRSA, a major global health problem and the leading cause of mortality from antibiotic-resistant infections in many countries. Here, we report a general approach to this problem exemplified by the design and synthesis of a vancomycin-d-octaarginine conjugate (V-r8) and investigation of its efficacy in addressing antibiotic-insensitive bacterial populations. V-r8 eradicated MRSA biofilm and persister cells in vitro, outperforming vancomycin by orders of magnitude. It also eliminated 97% of biofilm-associated MRSA in a murine wound infection model and displayed no acute dermal toxicity. This new dual-function conjugate displays enhanced cellular accumulation and membrane perturbation as compared to vancomycin. Based on its rapid and potent activit2018-01-01T00:00:00Z2018 Nov2025-04-22T04:39:10.992Z2019-08-04T07:43:43ZS-EPMC64307143038836610.1021/jacs.8b08711