Antibacterial activity of 2-alkynoic fatty acids against multidrug-resistant bacteria

• We carried out the total synthesis of four 2-AFAs and other derivatives.
• We determined the antibacterial activity of 2-AFAs against MRSA.
• Increasing the carbon chain length in 2-AFA, decrease its antibacterial activity.
• Triple bond at C-2 and carboxylic acid moieties in antibacterial 2-AFA are needed.
• Antibacterial properties of 2-AFAs are not mediated by micelle formation.

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.