Amino-Terminated Generation 2 Poly(amidoamine) Dendrimer as a Potential Broad-Spectrum, Nonresistance-Inducing Antibacterial Agent

Abstract

Abstract. The treatment of septicemia caused by antibiotic-resistant bacteria is a great challenge in the clinic. Because traditional antibiotics inevitably induce bacterial resistance, which is responsible for many treatment failures, there is an urgent need to develop novel antibiotic drugs. Amino-terminated Poly (amidoamine) dendrimers (PAMAM-NH 2 ) are reported to have antibacterial activities. However, previous studies focused on high generations of PAMAM-NH 2 , which have been found to exhibit high toxicities. The present study aimed to clarify whether low generations of PAMAM-NH 2 could be used as novel antibacterial agents. We found that generation 2 (G2.0) PAMAM-NH 2 showed significant antibacterial effects against antibiotic-sensitive and antibiotic-resistant strains but exhibited little toxicity to human gastric epithelial cells and did not induce antibiotic resistance in bacteria. Scanning and transmission electron microscopy analyses suggested that G2.0 PAMAM-NH 2 might inhibit the growth of bacteria by destroying their cell membranes. The administration of G2.0 PAMAM-NH 2 dosedependently improved the animal survival rate of mice infected with extended-spectrum beta lactamase-producing Escherichia coli (ESBL-EC) and of animals infected with a combination of ESBL-EC and methicillin-resistant Staphylococcus aureus. A treatment regimen of 10 mg/kg of G2.0 PAMAM-NH 2 starting 12 h before inoculation followed by 10 mg/kg at 0.5 h after inoculation rescued 100% of singly infected mice and 60% of multiply infected mice. The protective effects were associated with the reduction of the bacterial titers in the blood and with the morphological amelioration of infected tissues. These findings demonstrate that the G2.0 PAMAM-NH 2 is a potential broad-spectrum and nonresistance-inducing antibiotic agent with relatively low toxicity.

Mutagenicity Survey and Antibacterial Activity of Various Generations of Poly (Amid Amine) (PAMAM) Dendrimers and Algonac Acid Poly (Amid Amine) (PAMAM) Dendrimer Nano Composite G2 on Some Enteric Pathogenic Bacteria

“…In another study, Partoazar et al in Iran investigating 57 urine samples of medicine laboratory personals using the Ames test by S. typhimurium (TA98) showed that these samples caused mutagenicity (28). However, some studies showed that PAMAM dendrimers have genotoxicity effects on cells (25,29). In our study, Ames test showed that different generations of PAMAM (G2, G3, G4 and G5) had mutagenicity effects and reverted colonies were increased by higher-generation of PAMAM dendrimers.…”

“…Antibacterial mechanism of PAMAM is unknown, but several studies have proved that its antibacterial activity is related to PAMAM generation and G2 has better antibacterial activity (25). Cytoplasmic membrane of bacterial cell is a target for many antimicrobial agents.…”

R-Thanatin Inhibits Growth and Biofilm Formation of Methicillin-Resistant Staphylococcus epidermidis In Vivo and In Vitro

“…The cytotoxicity of R-thanatin to the human umbilical vein endothelial cells (HUVECs) was determined by a standard MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay (23,24). Briefly, cells (5 ϫ 10 3 cells/well) were seeded in a 96-well plate with 100 l Dulbecco's modified Eagle medium (DMEM) with 10% fetal bovine serum (FBS) in every well for 12 h and then exposed with or without R-thanatin at various concentrations (0.512 to 1024 g/ml) for 48 h. After drug treatment, MTT solution (final concentration, 0.5%) was added, and cells were incubated for another 4 h at 37°C.…”

“…The MIC of R-thanatin was determined against MRSE as described above. The MIC experiment was repeated for 15 days, as follows (23,25): one-half of the MIC well from the MIC result was diluted to a 0.5 McFarland standard in Mueller-Hinton broth (MHB) and then was diluted at 1:100 to a concentration of 5 ϫ 10 5 CFU/ml in MHB and used again for MIC determination in the subsequent generation. The relative MIC value was calculated from the ratio of the MIC obtained for the 15th subculture to that obtained for the first-time exposure.…”

The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro

“…The cytotoxicity of C-thanatin or L-thanatin for the human umbilical vein endothelial cells (HUVECs) was determined by a standard MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay (9,10). Briefly, cells (5 ϫ 10 3 cells/well) were seeded in a 96-well microtiter plate with 100 l Dulbecco's modified Eagle medium (DMEM) and 10% fetal bovine serum (FBS) in every well for 12 h and were then exposed with or without C-thanatin and L-thanatin at various concentrations (16 to 256 g/ml) for 48 h. After drug treatment, an MTT solution (final concentration, 0.5%) was added, and cells were incubated for another 4 h at 37°C.…”