2‐Methoxylated FA Display Unusual Antibacterial Activity Towards Clinical Isolates of Methicillin‐Resistant Staphylococcus aureus (CIMRSA) and Escherichia coli

Abstract

The naturally occurring (6Z)-(±)-2-methoxy-6-hexadecenoic acid (1) and (6Z)-(±)-2-methoxy-6-octadecenoic acid (2) were synthesized in 7–8 steps with 38% and 13% overall yields, respectively, by using an acetylide coupling approach, which made it possible to obtain a 100% cis-stereochemistry for the double bonds. In a similar fashion, the acetylenic analogs (±)-2-methoxy-6-hexadecynoic acid (3) and (±)-2-methoxy-6-octadecynoic acid (4) were also synthesized in 6–7 steps with 48% and 16% overall yields, respectively. The antibacterial activity of acids 1–4 was determined against clinical isolates of methicillin-resistant Staphylococcus aureus (ClMRSA) and E. coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17–37 µg/mL, in sharp contrast to the 6-octadecynoic acid, which was not bactericidal at all. On the other hand, acids 1 and 3 were the only acids that displayed antibacterial activity towards E. coli, but 1 stood out as the best candidate with an IC50 of 21 µg/mL. The critical micelle concentrations (CMCs) of acids 1–4 were also determined. The C18 acids 2 and 4 displayed a five-fold lower CMC (15–20 µg/mL) than the C16 analogs 1 and 3 (70–100 µg/mL), indicating that 4 exerts its antibacterial activity in a micellar state. None of the studied acids were inhibitory towards S. aureus DNA gyrase discarding this type of enzyme inhibition as a possible antibacterial mechanism. It was concluded that the combination of α-methoxylation and C-6 unsaturation increases the bactericidal activity of the C16 and C18 FA towards the studied bacterial strains. Acids 1 and 4 stand out as viable candidates to be used against E. coli and CIMRSA, respectively.

Antibacterial Activity of Hexadecynoic Acid Isomers toward Clinical Isolates of Multidrug‐Resistant Staphylococcus aureus

“…Once the bacterial characterization tests were performed, microdilution susceptibility tests were carried out as described before (Carballeira et al, ; Sanabria‐Rios et al, , ). Table shows the antibacterial activity of aFA against MRSA ATCC 43300 and three CIMRSA strains.…”

“…Several studies have reported the potential of unsaturated fatty acids as antibacterial agents (Carballeira et al, 1998(Carballeira et al, , 2002(Carballeira et al, , 2006(Carballeira et al, , 2017Konthikamee et al, 1982;Morbidoni et al, 2006;Sanabria-Rios et al, 2014. For example, in a study performed by Carballeira et al, 1998, the (Z)-2-methoxy-5-hexadecenoic and (Z)-2-methoxy-6-hexadecenoic acids were biologically active against S. aureus and Streptococcus faecalis at minimal inhibitory concentrations (MIC) of 0.35 μM.…”

“…For example, in a study performed by Carballeira et al, 1998, the (Z)-2-methoxy-5-hexadecenoic and (Z)-2-methoxy-6-hexadecenoic acids were biologically active against S. aureus and Streptococcus faecalis at minimal inhibitory concentrations (MIC) of 0.35 μM. In a more recent study, it was demonstrated that the (AE)-2-methoxy-6-octadecynoic acid inhibited MRSA at MIC values ranging between 31.3 and 62.5 μg/mL (Carballeira et al, 2017).…”

“…Despite the fact that several studies addressing the antibacterial activity of 2‐aFA exist (Carballeira et al, , ; Carballeira et al, ; Morbidoni et al, ; Sanabria‐Rios et al, ; Vilchèze et al, ), further studies are needed to better understand the chemical and structural characteristics required to improve the antibacterial activity of aFA as well as to understand their mechanism in gram‐positive bacteria. In the present study, the synthesis of several analogs of 1 containing a triple bond at either C‐3, C‐6, C‐8, C‐9, C‐10, and C‐12 was undertaken to determine the effect of the triple bond position in the antibacterial activity toward clinical isolates of MRSA (CIMRSA).…”

Application of a Newly Developed Chitosan/Oleic Acid Edible Coating for Extending Shelf-Life of Fresh Pork

“…Out of FAs, oleic acid (a monounsaturated FA, C18:1n-9) possesses a potent activity against both spoilage and pathogenic bacteria (e.g., Staphylococcus aureus, E. coli, Helicobacter, Clostridium and Salmonella species etc.) [22][23][24]. More importantly, reports have shown that a higher content of oleic acid is associated with better flavor characteristics of meat [25], since it contributes significantly to the development of cooked meat aromas [26].…”