2. Academic Validation
  3. Antibiotic-Polymer Self-Assembled Nanocomplex to Reverse Phenotypic Resistance of Bacteria toward Last-Resort Antibiotic Colistin

Antibiotic-Polymer Self-Assembled Nanocomplex to Reverse Phenotypic Resistance of Bacteria toward Last-Resort Antibiotic Colistin

  • ACS Nano. 2023 Aug 3. doi: 10.1021/acsnano.3c00981.
Huimin Zhao 1,  Lan-Lan Zhong 2 3,  Chuan Yang 4,  Ning Tang 1,  Yanwei He 1,  Wan He 5,  Zihan Zhao 2 3,  Changbu Wu 2 3,  Peiyan Yuan 1,  Yi Yan Yang 4 6,  Guo-Bao Tian 2 3 7,  Xin Ding 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China.
  • 2 Department of Immunology and Microbiology, Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, China.
  • 4 Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Centros #06-01, Singapore 138669, Singapore.
  • 5 Chengdu Medical College, Chengdu 610000, China.
  • 6 Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119288, Singapore.
  • 7 Department of Immunology, School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China.
PMID: 37534992 DOI: 10.1021/acsnano.3c00981
Abstract

Colistin is the last-resort Antibiotic to treat multidrug-resistant (MDR) Gram-negative Bacterial infections that are untreatable by other clinically available Antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., Bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an Antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or Antibiotic at equivalent doses exhibits no Antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis Infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic-polymer nanocomplex with two complementary Antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR Bacterial infections.

Keywords

antibiotic; bacterial infections; multidrug resistance; polymer; self-assembly.

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