2. Academic Validation
  3. Negatively charged nanodiscs for the reduction of toxicity and enhanced efficacy of polymyxin B against Acinetobacter baumannii sepsis

Negatively charged nanodiscs for the reduction of toxicity and enhanced efficacy of polymyxin B against Acinetobacter baumannii sepsis

  • Acta Biomater. 2024 Jun 18:S1742-7061(24)00331-3. doi: 10.1016/j.actbio.2024.06.017.
Penghe Wang 1,  Chunyang Xie 1,  Youwen Zhang 1,  Haibin Li 1,  Yun Lu 1,  Lang Sun 1,  Xinxin Hu 1,  Tongying Nie 1,  Congran Li 1,  Guoqing Li 1,  Xi Lu 1,  Jing Pang 1,  Xinyi Yang 1,  Liyan Yu 1,  Xue Li 2,  Xiukun Wang 3,  Xuefu You 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Division for Medicinal Microorganisms Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Division for Medicinal Microorganisms Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xueli@imb.pumc.edu.cn.
  • 3 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Division for Medicinal Microorganisms Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xiukunwang@imb.pumc.edu.cn.
  • 4 Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Division for Medicinal Microorganisms Related Strains, CAMS Collection Center of Pathogenic Microorganisms, Beijing 100050, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: xuefuyou@imb.pumc.edu.cn.
PMID: 38901753 DOI: 10.1016/j.actbio.2024.06.017
Abstract

The treatment of sepsis caused by multidrug-resistant (MDR) Gram-negative Bacterial infections remains challenging. With these pathogens exhibiting resistance to carbapenems and new generation cephalosporins, the traditional Antibiotic polymyxin B (PMB) has reemerged as a critical treatment option. However, its severe neurotoxicity and nephrotoxicity greatly limit the clinical application. Therefore, we designed negatively charged high-density lipoprotein (HDL) mimicking nanodiscs as a PMB delivery system, which can simultaneously reduce toxicity and enhance drug efficacy. The negative charge prevented the PMB release in physiological conditions and binding to cell membranes, significantly reducing toxicity in mammalian cells and mice. Notably, nanodisc-PMB exhibits superior efficacy than free PMB in sepsis induced by carbapenem-resistant Acinetobacter baumannii (CRAB) strains. Nanodisc-PMB shows promise as a treatment for carbapenem-resistant Gram-negative Bacterial sepsis, especially caused by Acinetobacter baumannii, and the nanodiscs could be repurposed for Other toxic Antibiotics as an innovative delivery system. STATEMENT OF SIGNIFICANCE: Multidrug-resistant Gram-negative bacteria, notably carbapenem-resistant Acinetobacter baumannii (CRAB), currently pose a substantial challenge due to the scarcity of effective treatments, rendering Polymyxins a last-resort Antibiotic option. However, their therapeutic application is significantly limited by severe neurotoxic and nephrotoxic side effects. Prevailing polymyxin delivery systems focus on either reducing toxicity or enhancing bioavailability yet fail to simultaneously achieve both. In this scenario, we have developed a distinctive HDL-mimicking nanodisc for polymyxin B, which not only significantly reduces toxicity but also improves efficacy against Gram-negative bacteria, especially in sepsis caused by CRAB. This research offers an innovative drug delivery system for polymyxin B. Such advancement could notably improve the therapeutic landscape and make a significant contribution to the arsenal against these notorious pathogens.

Keywords

Acinetobacter baumannii; multidrug-resistant; nanodisc; polymyxin B; sepsis.

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