Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers

Abstract

Dendrimers have emerged as topical microbicides to treat vaginal infections. This study explores the in-vitro, in-vivo antimicrobial activity of PAMAM dendrimers, and the associated mechanism. Interestingly, topical cervical application of 500 µg of generation-4 neutral dendrimer (G4-PAMAM-OH) showed potential to treat the Escherichia coli induced ascending uterine infection in guinea pig model of chorioamnionitis. Amniotic fluid collected from different gestational sacs of infected guinea pigs post treatment showed absence of E. coli growth in the cultures plated with it. The cytokine level [tumor necrosis factor (TNFα) and interleukin (IL-6 and IL-1β)] in placenta of the G4-PAMAM-OH treated animals were comparable to those in healthy animals while these were notably high in infected animals. Since, antibacterial activity of amine-terminated PAMAM dendrimers is known, the activity of hydroxyl and carboxylic acid terminated PAMAM dendrimers was compared with it. Though the G4-PAMAM-NH2 shows superior antibacterial activity, it was found to be cytotoxic to human cervical epithelial cell line above 10µg / mL, while the G4-PAMAM-OH was non cytotoxic upto 1mg / mL concentration. Cell integrity, outer (OM) and inner (IM) membrane permeabilization assays showed that G4-PAMAM-OH dendrimer efficiently changed the OM permeability, while G4-PAMAM-NH2 and G3.5-PAMAM-COOH damaged both OM and IM causing the bacterial lysis. The possible antibacterial mechanism are; G4-PAMAM-NH2 acts as polycation binding to the polyanionic lipopolysaccharide in E. coli, the G4-PAMAM-OH forms hydrogen bonds with the hydrophilic O-antigens in E. coli membrane and the G3.5-PAMAM-COOH acts as a polyanion, chelating the divalent ions in outer cell membrane of E. coli. This is the first study which shows that G4-PAMAM-OH dendrimer acts as an antibacterial agent.

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

“…2) and previous reports (30). The broad-spectrum antibacterial activity and toxicity to eukaryotic cells imply that PAMAM-NH 2 may disrupt cells irrespective of their species, and it has been suggested that PAMAM-NH 2 may damage cells through nonspecific physical mechanisms rather than by targeting specific molecules (19). The G2.0 PAMAM-NH 2 dendrimer is a polycation that may replace the divalent ions binding to the polyanions present in the cell membrane.…”

“…Chemical modifications of PAMAM-NH 2 dendrimers were demonstrated to reduce their toxicities, but these modifications simultaneously reduced the antibacterial activities of the PAMAM-NH 2 dendrimers (11,16). To date, antibacterial research on PAMAM-NH 2 dendrimers has been limited to topical (17)(18)(19) and drug carrier applications (20)(21)(22). Insufficient data are available to determine whether PAMAM-NH 2 dendrimers could be used systemically as antibacterial agents.…”

Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line

“…Many already are or may soon become useful tools with applications in various fields of biomedical science. Dendrimers could play a role as efficient drug, nucleic acid and contrast agent carriers [3], or they may be used as antipathogenic compounds [4][5][6]. In vitro studies have revealed that these nanoparticles possess the ability to inhibit the fibrillation and aggregation of proteins involved in neurodegenerative disorders [7][8][9].…”

Antimicrobial Activities of the Polypropylene Imine Dendrimer Aginst Bacteria Isolated From Rural Water Resources

“…This character refers to end amine groups in dendrimer structure which interact with negative charge of membrane or cytoplasm microorganism causes bacterial cell wall damage and finally, inhabitation of bacterial activity (21). However, the PPI-G2 dendrimer is an efficient antibacterial agent against both Gram-negative and Gram-positive bacteria.…”

“…Therefore, the end amino group in their structure is the cause of their microbicidal properties (20). Antimicrobial activity of dendrimers is related to some key factors such as dendrimer core type, dendrimer surface charge, their functional groups, dendrimer three-dimensional structure and its size (21). However, it is recognized that if site effects of dendrimers are cell walls or cell membranes, the anti-life stabilized on the dendrimers can be more effective (16).…”