A Dual-Function Antibiotic-Transporter Conjugate Exhibits Superior Activity in Sterilizing MRSA Biofilms and Killing Persister Cells.
Alexandra AntonoplisXiaoyu ZangMelanie A HuttnerKelvin K L ChongYu B LeeJulia Y CoManuel R AmievaKimberly A KlinePaul A WenderLynette CegelskiPublished in: Journal of the American Chemical Society (2018)
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.
Keyphrases
- methicillin resistant staphylococcus aureus
- staphylococcus aureus
- induced apoptosis
- pseudomonas aeruginosa
- cell cycle arrest
- candida albicans
- global health
- biofilm formation
- oxidative stress
- cancer therapy
- escherichia coli
- liver failure
- cystic fibrosis
- public health
- coronary artery disease
- hepatitis b virus
- pi k akt
- wound healing
- genetic diversity