2. Academic Validation
  3. Amphiphilic Dendrimer as Potent Antibacterial against Drug-Resistant Bacteria in Mouse Models of Human Infectious Diseases

Amphiphilic Dendrimer as Potent Antibacterial against Drug-Resistant Bacteria in Mouse Models of Human Infectious Diseases

  • ACS Infect Dis. 2024 Jan 19. doi: 10.1021/acsinfecdis.3c00425.
Noah King 1,  Dinesh Dhumal 2,  Shi Qian Lew 1,  Shanny Hsuan Kuo 1,  Christina Galanakou 2,  Myung Whan Oh 1,  Sook Yin Chong 1,  Nian Zhang 3,  Leo Tsz On Lee 3 4,  Zvi Hayouka 5,  Ling Peng 2,  Gee W Lau 1
Affiliations

Affiliations

  • 1 Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, United States.
  • 2 CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), UMR 7325, Equipe Labelisée Ligue Contre le Cancer, Aix Marseille University, Parc Scientifique et Technologique de Luminy 913, Marseille 13288, France.
  • 3 Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China.
  • 4 Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau, China.
  • 5 Institute of Biochemistry, Food Science and Nutrition, the Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew University of Jerusalem, Rehovot 76100, Israel.
PMID: 38241613 DOI: 10.1021/acsinfecdis.3c00425
Abstract

Modern medicine continues to struggle against antibiotic-resistant Bacterial pathogens. Among the pathogens of critical concerns are the multidrug-resistant (MDR) Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. These pathogens are major causes of nosocomial infections among immunocompromised individuals, involving major organs such as lung, skin, spleen, kidney, liver, and bloodstream. Therefore, novel approaches are direly needed. Recently, we developed an amphiphilic dendrimer DDC18-8A exhibiting high Antibacterial and antibiofilm efficacy in vitro. DDC18-8A is composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing amine terminals, exerting its Antibacterial activity by attaching and inserting itself into Bacterial membranes to trigger Cell Lysis. Here, we examined the pharmacokinetics and in vivo toxicity as well as the Antibacterial efficacy of DDC18-8A in mouse models of human infectious diseases. Remarkably, DDC18-8A significantly reduced the Bacterial burden in mouse models of acute pneumonia and bacteremia by P. aeruginosa, methicillin-resistant S. aureus (MRSA), and carbapenem-resistant K. pneumoniae and neutropenic soft tissue Infection by P. aeruginosa and MRSA. Most importantly, DDC18-8A outperformed pathogen-specific Antibiotics against all three pathogens by achieving a similar Bacterial clearance at 10-fold lower therapeutic concentrations. In addition, it showed superior stability and biodistribution in vivo, with excellent safety profiles yet without any observable abnormalities in histopathological analysis of major organs, blood serum biochemistry, and hematology. Collectively, we provide strong evidence that DDC18-8A is a promising alternative to the currently prescribed Antibiotics in addressing challenges associated with nosocomial infections by MDR pathogens.

Keywords

Klebsiella pneumoniae; Pseudomonas aeruginosa; Staphylococcus aureus; amphiphilic dendrimer; in vivo efficacy.

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