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  3. Development of membrane-targeting TPP+-chloramphenicol conjugates to combat methicillin-resistant staphylococcus aureus (MRSA) infections

Development of membrane-targeting TPP+-chloramphenicol conjugates to combat methicillin-resistant staphylococcus aureus (MRSA) infections

  • Eur J Med Chem. 2023 Nov 27:264:115973. doi: 10.1016/j.ejmech.2023.115973.
Tao Li 1,  Xiaoli He 2,  Wenlan Tao 2,  Ruixue Zhang 1,  Qiaolin He 1,  Hongzhi Gong 1,  Ye Liu 1,  Dong Luo 1,  Maojie Zhang 1,  Cheng Zou 1,  Shao-Lin Zhang 3,  Yun He 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China.
  • 2 Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, 266 Fangzheng Ave, Shuitu Technology Development Zone, Beibei, Chongqing, 400714, PR China.
  • 3 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China; State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, 518055, PR China. Electronic address: [email protected].
  • 4 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, No. 55 Daxuecheng South Rd., Shapingba, Chongqing, 401331, PR China; Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, 266 Fangzheng Ave, Shuitu Technology Development Zone, Beibei, Chongqing, 400714, PR China. Electronic address: [email protected].
PMID: 38096652 DOI: 10.1016/j.ejmech.2023.115973
Abstract

Infections caused by drug-resistant bacteria have become a new challenge in Infection treatment, gravely endangering public health. Chloramphenicol (CL) is a well-known Antibiotic which has lost its efficacy due to Bacterial resistance. To address this issue, herein we report the design, synthesis and biological evaluations of novel triphenylphosphonium chloramphenicol conjugates (TPP+-CL). Study results indicated that compounds 39 and 42 possessed remarkable Antibacterial effects against clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 2 μg/mL, while CL was inactive to the tested MRSA strains. In addition, these conjugates exhibited rapid bactericidal properties and low toxicity, and did not readily induced Bacterial resistance, obviously outperforming the parent drug CL. In a mouse model infected with a clinically isolated MRSA strain, compound 39 at a dose of 20 mg/kg exhibited a comparable or even better in vivo anti-MRSA efficacy than the golden standard drug vancomycin, while no toxicity was observed.

Keywords

Drug-resistance; Membrane disruption; Triphenylphosphonium cation.

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