Comparing micellar, hemolytic, and antibacterial properties of di- and tricarboxyl dendritic amphiphiles

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• 作者：Bhadreshkumar B. Maisuria^a ; ^† ; ; Marcelo L. Actis^a ; ^‡ ; ; Shauntrece N. Hardrict^a ; ^§ ; ; Joseph O. Falkinham III^b ; Michael F. Cole^c ; Ronald L. Cihlar^c ; Stephen M. Peters^d ; Richard V. Macri^a ; ^¶ ; ; Eko W. Sugandhi^a ; ^|| ; André ; A. Williams^a ; ^† ; † ; ; Michael A. Poppe^b ; Alan R. Esker^a ; Richard D. Gandour^a ; ^{gandour@vt.edu"" rel=""nofollow}
• 关键词：Dendritic amphiphiles ; Staphylococcus aureus ; MRSA ; Critical micelle concentrations ; Hemolytic activities
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：1 May 2011
• 年：2011
• 卷：19
• 期：9
• 页码：2918-2926
• 全文大小：648 K

文摘

Homologous dicarboxyl dendritic amphiphiles—RCONHC(CH₃)(CH₂CH₂COOH)₂, 4(n); and ROCONHC(CH₃)(CH₂CH₂COOH)₂, 5(n), where R = n-C_nH_2n+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, EC₁₀) in phosphate-buffered saline (PBS). Log CMC showed a linear dependence on chain length (n); the longest chain in each series had the lowest CMC—in triethanolamine: 4(21), 180 μM and 5(22), 74 μM and at pH 7.4: 4(21), 78 μM and 5(22), 33 μM. These two series, 4(n) and 5(n), and three series of homologous tricarboxyl dendritic amphiphiles—RCONHC(CH₂CH₂COOH)₃, 1(n); ROCONHC(CH₂CH₂COOH)₃, 2(n); RNHCONHC(CH₂CH₂COOH)₃, 3(n), where R = n-C_nH_2n+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 (2.2–3.4 μg/mL) against S. aureus (vancomycin, MIC = 0.25 μg/mL). These four plus 1(21), 2(20), 2(22), and 3(20) exhibited the strongest antibacterial activity (1.7–6.8 μg/mL) against MRSA (vancomycin, MIC = 0.25 μg/mL). The MICs of these amphiphiles against six clinical MRSA were similar to those against the ATCC strain. In PBS, EC₁₀s of the most active homologues ranged from 7 to 18 μg/mL and 18 to 220 μg/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 (9–36 μg/mL, 18–72 μM) of ten amphiphiles were measured by microdilution (log 2 progression) with dye-covered beads. The EC₁₀s were similar to those in PBS. The MICs of most amphiphiles (14–72 μg/mL) and vancomycin (1.1–2.2 μg/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 1.1 μg/mL compared to vancomycin (2.2 μg/mL). With CMC (9–18 μg/mL) and EC₁₀ (16 μg/mL) values higher than the MIC, 5(18) was discovered as a lead for further development.