A Dual-Function Antibiotic-Transporter Conjugate Exhibits Superior Activity in Sterilizing MRSA Biofilms and Killing Persister Cells
2018
Antonoplis, Alexandra | Zang, Xiaoyu | Huttner, Melanie A. | Chong, Kelvin K. L. | Lee, Yu B. | Co, Julia Y. | Amieva, Manuel R. | Kline, Kimberly A. | Wender, Paul A. | Cegelski, Lynette
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 activity against biofilm and persister cells, V–r8 is a promising agent against clinical MRSA infections.
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