ABSTRACT
In the present study, the structural characteristics that impart antibacterial activity to C16 alkynoic fatty acids (aFA) were further investigated. The syntheses of hexadecynoic acids (HDA) containing triple bonds at C-3, C-6, C-8, C-9, C-10, and C-12 were carried out in four steps and with an overall yield of 34-78%. In addition, HDA analogs containing a sulfur atom at either C-4 or C-5 were also prepared in 69-77% overall yields, respectively. Results from this study revealed that the triple bond at C-2 is pivotal for the antibacterial activity displayed by 2-HDA, while the farther the position of the triple bond from the carbonyl group, the lower its bactericidal activity against gram-positive bacteria, including clinical isolates of methicillin-resistant Staphylococcus aureus (CIMRSA) strains. The potential of 2-HDA as an antibacterial agent was also assessed in five CIMRSA strains that were resistant to Ciprofloxacin (Cipro) demonstrating that 2-HDA was the most effective treatment in inhibiting their growth when compared with either Cipro alone or equimolar combinations of Cipro and 2-HDA. Moreover, it was proved that the inhibition of S. aureus DNA gyrase can be linked to the antibacterial activity displayed by 2-HDA. Finally, it was determined that the ability of HDA analogs to form micelles can be linked to their decreased activity against gram-positive bacteria, since critical micellar concentrations (CMC) between 50 and 300 µg/mL were obtained.
Subject(s)
Alkynes/pharmacology , Anti-Bacterial Agents/pharmacology , Fatty Acids, Unsaturated/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Staphylococcal Infections/microbiology , Alkynes/chemistry , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Ciprofloxacin/pharmacology , DNA Gyrase/metabolism , Drug Resistance, Multiple, Bacterial/drug effects , Fatty Acids, Unsaturated/chemistry , Gas Chromatography-Mass Spectrometry , Humans , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Microbial Sensitivity Tests , Microbial Viability/drug effects , Structure-Activity RelationshipABSTRACT
The first study aimed at determining the structural characteristics needed to prepare antibacterial 2-alkynoic fatty acids (2-AFAs) was accomplished by synthesizing several 2-AFAs and other analogs in 18-76% overall yields. Among all the compounds tested, the 2-hexadecynoic acid (2-HDA) displayed the best overall antibacterial activity against Gram-positive Staphylococcus aureus (MIC=15.6 µg/mL), Staphylococcus saprophyticus (MIC=15.5 µg/mL), and Bacillus cereus (MIC=31.3 µg/mL), as well as against the Gram-negative Klebsiella pneumoniae (7.8 µg/mL) and Pseudomonas aeruginosa (MIC=125 µg/mL). In addition, 2-HDA displayed significant antibacterial activity against methicillin-resistant S. aureus (MRSA) ATCC 43300 (MIC=15.6 µg/mL) and clinical isolates of MRSA (MIC=3.9 µg/mL). No direct relationship was found between the antibacterial activity of 2-AFAs and their critical micelle concentration (CMC) suggesting that the antibacterial properties of these fatty acids are not mediated by micelle formation. It was demonstrated that the presence of a triple bond at C-2 and the carboxylic acid moiety in 2-AFAs are important for their antibacterial activity. 2-HDA has the potential to be further evaluated for use in antibacterial formulations.
