title: Comparing micellar, hemolytic, and antibacterial properties of di- and tricarboxyl dendritic amphiphiles.
abstract: Homologous dicarboxyl dendritic amphiphiles-RCONHC(CH(3))(CH(2)CH(2)COOH)(2), 4(n); and ROCONHC(CH(3))(CH(2)CH(2)COOH)(2), 5(n), where R=n-C(n)H(2)(n)(+1) and n=13-22 carbon atoms-were synthesized. Critical micelle concentrations (CMCs) in aqueous triethanolamine solutions and at pH 7.4 were measured along with hemolytic activity (effective concentrations, EC(10)) in phosphate-buffered saline (PBS). LogCMC showed a linear dependence on chain length (n); the longest chain in each series had the lowest CMC-in triethanolamine: 4(21), 180μM and 5(22), 74μM and at pH 7.4: 4(21), 78μM and 5(22), 33μM. These two series, 4(n) and 5(n), and three series of homologous tricarboxyl dendritic amphiphiles-RCONHC(CH(2)CH(2)COOH)(3), 1(n); ROCONHC(CH(2)CH(2)COOH)(3), 2(n); RNHCONHC(CH(2)CH(2)COOH)(3), 3(n), where R=n-C(n)H(2)(n)(+1) and n=13-22 carbon atoms-were tested for growth inhibition of Staphylococcus aureus strain ATCC 6358 and methicillin-resistant S. aureus (MRSA) strain ATCC 43330 by microdilution in 0.1-strength brain heart infusion broth (BHIB). Amphiphiles 4(19), 4(21), 5(18), and 5(20) showed the strongest antibacterial activity (2.2-3.4μg/mL) against S. aureus (vancomycin, MIC=0.25μg/mL). These four plus 1(21), 2(20), 2(22), and 3(20) exhibited the strongest antibacterial activity (1.7-6.8μg/mL) against MRSA (vancomycin, MIC=0.25μg/mL). The MICs of these amphiphiles against six clinical MRSA were similar to those against the ATCC strain. In PBS, EC(10)s of the most active homologues ranged from 7 to 18μg/mL and 18 to 220μg/mL for di- and tricarboxyl dendritic amphiphiles, respectively. To assess the potential safety of using dendritic amphiphiles as drugs, measurements of micellar and hemolytic properties were conducted in the same medium (full-strength BHIB) that was used for antibacterial activity. The CMCs (9-36μg/mL, ∼18-72μM) of ten amphiphiles were measured by microdilution (log2 progression) with dye-covered beads. The EC(10)s were similar to those in PBS. The MICs of most amphiphiles (14-72μg/mL) and vancomycin (1.1-2.2μg/mL) against both S. aureus and MRSA increased significantly compared to the MICs measured in 0.1-strength BHIB. The one exception, 5(18), had an MIC against S. aureus of 1.1μg/mL compared to vancomycin (2.2μg/mL). With CMC (9-18μg/mL) and EC(10) (16μg/mL) values higher than the MIC, 5(18) was discovered as a lead for further development.
authors.affiliation: Department of Chemistry, M.C. 0212, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Bhadreshkumar B
authors.initials: BB
authors.lastname: Maisuria
authors.forename: Marcelo L
authors.initials: ML
authors.lastname: Actis
authors.forename: Shauntrece N
authors.initials: SN
authors.lastname: Hardrict
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Falkinham
authors.forename: Michael F
authors.initials: MF
authors.lastname: Cole
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Cihlar
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Peters
authors.forename: Richard V
authors.initials: RV
authors.lastname: Macri
authors.forename: Eko W
authors.initials: EW
authors.lastname: Sugandhi
authors.forename: André A
authors.initials: AA
authors.lastname: Williams
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poppe
authors.forename: Alan R
authors.initials: AR
authors.lastname: Esker
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gandour
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry* / Q000494:pharmacology; D006461:Hemolysis; D006538:Heptanoic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008823:Micelles; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: C560334:4-methyl-4-(octadecyloxycarbonylamino)heptanedioic acid; D000900:Anti-Bacterial Agents; D050091:Dendrimers; D006538:Heptanoic Acids; D008823:Micelles