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

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.

Comparing anti-HIV, antibacterial, antifungal, micellar, and cytotoxic properties of tricarboxylato dendritic amphiphiles.

Three series of homologous 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(2n+1) and n = 13-22 carbon atoms--were assayed for their potential to serve as antimicrobial components in a topical vaginal formulation. Comparing epithelial cytotoxicities to the ability of these homologues to inhibit HIV, Neisseria gonorrhoeae, and Candida albicans provided a measure of their prophylactic/therapeutic potential. Measurements of the ability to inhibit Lactobacillus plantarum, a beneficial bacterium in the vagina, and critical micelle concentrations (CMCs), an indicator of the potential detergency of these amphiphiles, provided additional assessments of safety. Several amphiphiles from each homologous series had modest anti-HIV activity (EC(50) = 110-130 microM). Amphiphile 2(18) had the best anti-Neisseria activity (MIC =65 microM), while 1(19) and 1(21) had MICs against C. albicans of 16 and 7.7 microM, respectively. Two measures of safety showed promise as all compounds had relatively low cytotoxic activity (EC(50) = 210-940 microM) against epithelial cells and low activity against L. plantarum, 1(n), 2(n), and 3(n) had MICs490, 1300, and 940 microM, respectively. CMCs measured in aqueous triethanolamine and in aqueous potassium hydroxide showed linear dependences on chain length. As expected, the longest chain in each series had the lowest CMC-in triethanolamine: 1(21), 1500 microM; 2(22), 320 microM; 3(22), 340 microM, and in potassium hydroxide: 1(21), 130 microM; 3(22), 40 microM. The CMC in triethanolamine adjusted to pH 7.4 was 400 microM for 1(21) and 3900 microM for 3(16). The promising antifungal activity, low activity against L. plantarum, relatively high CMCs, and modest epithelial cytotoxicity in addition to their anti-Neisseria properties warrant further design studies with dendritic amphiphiles to improve their safety indices to produce suitable candidates for antimicrobial vaginal products.

Antibacterial activities of dendritic amphiphiles against nontuberculous mycobacteria.

The anti-mycobacterial activities of nine series of dicarboxyl and tricarboxyl dendritic amphiphiles with one alkyl, two alkyl, and cholestanyl tails against Mycobacterium abscessus, Mycobacterium avium, Mycobacterium chelonae, Mycobacterium marinum and Mycobacterium smegmatis have been measured. The dendritic amphiphiles overcame the limited aqueous solubility of natural long-chain fatty acids, alcohols, and amines to enable profiling the susceptibilities of the different mycobacterial species to the physicochemical properties of these amphiphiles. Several dendritic amphiphiles showed strong anti-mycobacterial activity with high critical micelle concentrations and low hemolytic activities thereby offering platforms for the development of antibiotics of higher activity against nontuberculous mycobacteria.