Chemical conjugation of 2-hexadecynoic acid to C5-curcumin enhances its antibacterial activity against multi-drug resistant bacteria.
The first total synthesis of a C5-curcumin-2-hexadecynoic acid (C5-Curc-2-HDA, 6) conjugate was successfully performed. Through a three-step synthetic route, conjugate 6 was obtained in 13% overall yield and tested for antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) strains. Our results revealed that 6 was active against eight MRSA strains at MICs that range between 31.3 and 62.5 μg/mL. It was found that the presence of 2-hexadecynoic acid (2-HDA, 4) in conjugate 6 increased 4-8-fold its antibacterial activity against MRSA strains supporting our hypothesis that the chemical connection of 4 to C5-curcumin (2) increases the antibacterial activity of 2 against Gram-positive bacteria. Combinational index (CIn) values that range between 1.6 and 2.3 were obtained when eight MRSA strains were treated with an equimolar mixture of 2 and 4. These results demonstrated that an antagonistic effect is taking place. Finally, it was investigated whether conjugate 6 can affect the replication process of S. aureus, since this compound inhibited the supercoiling activity of the S. aureus DNA gyrase at minimum inhibitory concentrations (MIC) of 250 μg/mL (IC50=100.2±13.9 μg/mL). Moreover, it was observed that the presence of 4 in conjugate 6 improves the anti-topoisomerase activity of 2 towards S. aureus DNA gyrase, which is in agreement with results obtained from antibacterial susceptibility tests involving MRSA strains.
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan 00919, Puerto Rico. Electronic address: dsanabria@intermetro.edu.
David J
DJ
Sanabria-Ríos
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan 00919, Puerto Rico.
Yaritza
Y
Rivera-Torres
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan 00919, Puerto Rico.
Joshua
J
Rosario
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan 00919, Puerto Rico.
Ricardo
R
Gutierrez
Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, San Juan 00919, Puerto Rico.
Yeireliz
Y
Torres-García
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan 00931-3346, Puerto Rico.
Nashbly
N
Montano
Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón 00960, Puerto Rico.
Gabriela
G
Ortíz-Soto
Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón 00960, Puerto Rico.
Eddy
E
Ríos-Olivares
Department of Microbiology and Immunology, Universidad Central del Caribe School of Medicine, PO Box 60327, Bayamón 00960, Puerto Rico.
José W
JW
Rodríguez
Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan 00931-3346, Puerto Rico.
Néstor M
NM
Carballeira
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D027081:DNA Gyrase / Q000737:chemistry; D004278:DNA, Superhelical / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D013211:Staphylococcus aureus / Q000201:enzymology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D014709:Vero Cells
D000480:Alkynes; D000900:Anti-Bacterial Agents; C000609661:C5-curcumin-2-hexadecynoic acid; D004278:DNA, Superhelical; D005231:Fatty Acids, Unsaturated; D059005:Topoisomerase II Inhibitors; C031203:2-hexadecynoic acid; D027081:DNA Gyrase; D003474:Curcumin
Antagonism; Antibacterial agents; C5-curcuminoids synthesis; DNA gyrase; MRSA