Amphiphilic Dendrimer as Potent Antibacterial against Drug-Resistant Bacteria in Mouse Models of Human Infectious
Noah King1, Dinesh Dhumal2, Shi Qian Lew1
1Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, United States.
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.
Insights
A novel amphiphilic dendrimer, DDC18-8A, effectively combats multidrug-resistant (MDR) bacterial infections like Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae in mice. This promising compound shows superior efficacy and safety compared to conventional antibiotics.
Area of Science:
- Biochemistry
- Pharmacology
- Infectious Diseases
Background:
- Antibiotic resistance poses a significant global health threat, particularly from multidrug-resistant (MDR) pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae.
- These MDR pathogens are primary causes of difficult-to-treat nosocomial infections in immunocompromised individuals, affecting multiple organ systems.
Purpose of the Study:
- To evaluate the pharmacokinetic properties, in vivo toxicity, and antibacterial efficacy of the amphiphilic dendrimer DDC18-8A against critical MDR bacterial pathogens.
- To compare the therapeutic potential of DDC18-8A with existing pathogen-specific antibiotics in preclinical mouse models.
Main Methods:
- Dendrimer DDC18-8A, an amphiphilic molecule with antibacterial and antibiofilm properties, was administered to mouse models.
- Efficacy was assessed in models of acute pneumonia, bacteremia, and neutropenic soft tissue infection caused by P. aeruginosa, MRSA, and carbapenem-resistant K. pneumoniae.
- Pharmacokinetics, biodistribution, and toxicity (histopathology, serum biochemistry, hematology) were evaluated in vivo.
Main Results:
- DDC18-8A significantly reduced bacterial burden in all tested infection models.
- The dendrimer demonstrated superior efficacy to conventional antibiotics, achieving comparable bacterial clearance at 10-fold lower concentrations.
- DDC18-8A exhibited favorable in vivo stability, biodistribution, and an excellent safety profile with no observed organ toxicity.
Conclusions:
- DDC18-8A represents a promising novel therapeutic candidate for treating infections caused by MDR bacterial pathogens.
- Its potent antibacterial activity, favorable pharmacokinetics, and safety profile suggest it could be a valuable alternative to current antibiotic treatments for nosocomial infections.
