TY - JOUR
T1 - Amphiphilic Dendrimer as Potent Antibacterial against Drug-Resistant Bacteria in Mouse Models of Human Infectious Diseases
AU - King, Noah
AU - Dhumal, Dinesh
AU - Lew, Shi Qian
AU - Kuo, Shanny Hsuan
AU - Galanakou, Christina
AU - Oh, Myung Whan
AU - Chong, Sook Yin
AU - Zhang, Nian
AU - Lee, Leo Tsz On
AU - Hayouka, Zvi
AU - Peng, Ling
AU - Lau, Gee W.
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/2/9
Y1 - 2024/2/9
N2 - 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.
AB - 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.
KW - Klebsiella pneumoniae
KW - Pseudomonas aeruginosa
KW - Staphylococcus aureus
KW - amphiphilic dendrimer
KW - in vivo efficacy
UR - http://www.scopus.com/inward/record.url?scp=85183034254&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.3c00425
DO - 10.1021/acsinfecdis.3c00425
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 38241613
AN - SCOPUS:85183034254
SN - 2373-8227
VL - 10
SP - 453
EP - 466
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 2
ER -