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

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Lipids

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 Escherichia coli. Among the series of compounds, acid 4 was the most active bactericide towards CIMRSA displaying IC50s (half maximal inhibitory concentrations) between 17 and 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 discounting 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.

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Abbreviations

ClMRSA:

Clinical isolates of methicillin-resistant Staphylococcus aureus

CMC:

Critical micelle concentration

DCM:

Dichloromethane

DMI:

1,3-Dimethyl-2-imidazolidinone

DMSO:

Dimethyl sulfoxide

FA:

Fatty acid(s)

GC/MS:

Gas chromatography-mass spectrometry

IC50 :

Half maximal inhibitory concentration

MIC:

Minimum inhibitory concentration

PCC:

Pyridinium chlorochromate

PTSA:

p-Toluenesulfonic acid

Rel DNA:

Relaxed deoxyribonucleic acid

SEM:

Standard error of the mean

SC DNA:

Super coiled deoxyribonucleic acid

TSI:

Trypticase Soy Broth

THF:

Tetrahydrofuran

TMSCN:

Trimethylsilyl cyanide

UPLC-MS:

Ultra high performance liquid chromatography-mass spectrometry

References

  1. Desbois AP, Smith VJ (2010) Antibacterial free fatty acids: activities, mechanisms of action and biotechnological potential. Appl Microbiol Biotechnol 85:1629–1642

    Article  CAS  PubMed  Google Scholar 

  2. Carballeira NM (2002) New advances in the chemistry of methoxylated lipids. Prog Lipid Res 41:437–456

    Article  CAS  PubMed  Google Scholar 

  3. Carballeira NM, Oyola D, Vicente J, Rodríguez AD (2007) Identification of novel a-methoxylated phospholipid fatty acids in the Caribbean sponge Erylus goffrilleri. Lipids 42:1047–1053

    Article  CAS  PubMed  Google Scholar 

  4. Carballeira NM, Montano N, Amador LA, Rodríguez AD, Golovko MY, Golovko SA, Reguera RM, Álvarez-Velilla R, Balana-Fouce R (2016) Novel very long-chain α-methoxylated Δ5,9 fatty acids from the sponge Asteropus niger are effective inhibitors of topoisomerase IB. Lipids 51:245–256

    Article  CAS  PubMed  Google Scholar 

  5. Carballeira NM, Cruz H, Orellano EA, González FA (2003) The first total synthesis of the marine fatty acid (±)-2-methoxy-13-methyltetradecanoic acid: a cytotoxic fatty acid to leukemia cells. Chem Phys Lipids 126:149–153

    Article  CAS  PubMed  Google Scholar 

  6. Orellano EA, Cartagena MM, Rosado K, Carballeira NM (2013) Synthesis of the novel (±)-2-methoxy-6-icosynoic acid- a fatty acid that induces death of neuroblastoma cells. Chem Phys Lipids 172–173:14–19

    Article  PubMed  Google Scholar 

  7. Carballeira NM, Ortiz D, Parang K, Sardari S (2004) Total synthesis and in vitro-antifungal activity of (±)-2-methoxytetradecanoic acid. Arch Pharm Pharm Med Chem 337:152–155

    Article  CAS  Google Scholar 

  8. Carballeira NM, Miranda C, Parang K (2009) The first total synthesis of (±)-4-methoxydecanoic acid: a novel antifungal fatty acid. Tetrahedron Lett 50:5699–5700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Carballeira NM, Emiliano A, Hernández-Alonso N, González FA (1998) Facile total synthesis and antimicrobial activity of the marine fatty acids (Z)-2-methoxy-5-hexadecenoic acid and (Z)-2-methoxy-6-hexadecenoic acid. J Nat Prod 61:1543–1546

    Article  CAS  PubMed  Google Scholar 

  10. Carballeira NM, Cruz H, Kwong CD, Wan B, Franzblau S (2004) 2-Methoxylated fatty acids in marine sponges: defense mechanism against mycobacteria. Lipids 39:675–680

    Article  CAS  PubMed  Google Scholar 

  11. Parsons JB, Yao J, Frank MW, Jackson P, Rock CO (2012) Membrane disruption by antimicrobial fatty acids releases low-molecular weight proteins from Staphylococcus aureus. J Bacteriol 194:5294–5304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Carballeira NM, Alicea J (2002) Novel methoxylated FA from the Caribbean sponge Spheciospongia cuspidifera. Lipids 37:305–308

    Article  CAS  PubMed  Google Scholar 

  13. Valicenti AJ, Pusch FJ, Holman RT (1985) Synthesis of octadecynoic acids and [1-14C] labeled isomers of octadecenoic acids. Lipids 20:234–242

    Article  CAS  PubMed  Google Scholar 

  14. Sanabria-Ríos DJ, Rivera-Torres Y, Maldonado-Domínguez G, Domínguez I, Ríos C, Díaz D, Rodríguez JW, Altieri-Rivera JS, Ríos-Olivares E, Cintrón G, Montano N, Carballeira NM (2014) Antibacterial activity of 2-alkynoic fatty acids against multidrug resistant bacteria. Chem Phys Lipids 178:84–91

    Article  PubMed  Google Scholar 

  15. Sanabria-Ríos DJ, Rivera-Torres Y, Rosario J, Gutierrez R, Torres-García Y, Montano N, Ortíz-Soto G, Ríos-Olivares E, Rodríguez JW, Carballeira NM (2015) Chemical conjugation of 2-hexadecynoic acid to C5-Curcumin enhances its antibacterial activity against multi-drug resistant bacteria. Bioorg Med Chem Lett 25:5067–5071

    Article  PubMed  PubMed Central  Google Scholar 

  16. Courtney HS, Andrew-Simpson W, Beachey EH (1986) Relationship of critical micelle concentration of bacterial lipoteichoic acids to biological activities. Infect Immun 51:414–418

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ferrero L, Cameron B, Manse B, Lagneaux D, Crouzet J, Famechon A, Blanche F (1994) Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol Microbiol 13:641–653

    Article  CAS  PubMed  Google Scholar 

  18. Peters JS, Chin C-K (2003) Inhibition of photosynthetic electron transport by palmitoleic acid is partially correlated to loss of thylakoid membrane proteins. Plant Physiol Biochem 41:117–124

    Article  CAS  Google Scholar 

  19. Więckowski MR, Wojtczak L (1998) Fatty acid-induced uncoupling of oxidative phosphorylation is partly due to opening of the mitochondrial permeability transition pore. FEBS Lett 423:339–342

    Article  PubMed  Google Scholar 

  20. Galbraith H, Miller TB (1973) Physiological effects of long chain fatty acids on bacterial cells and their protoplasts. J Appl Bacteriol 36:647–658

    Article  CAS  PubMed  Google Scholar 

  21. Knapp HR, Melly MA (1986) Bactericidal effects of polyunsaturated fatty acids. J Infect Dis 154:84–94

    Article  CAS  PubMed  Google Scholar 

  22. Zheng CJ, Yoo JS, Lee TG, Cho HY, Kim YH, Kim WG (2005) Fatty acid synthesis is a target for antibacterial activity of unsaturated fatty acids. FEBS Lett 579:5157–5162

    Article  CAS  PubMed  Google Scholar 

  23. Cartron ML, England SR, Chiriac AL, Josten M, Turner R, Rauter Y, Hurd A, Sahl H-G, Jones S, Foster SJ (2014) Bactericidal activity of the human skin fatty acid cis-6-hexadecenoic acid on Staphylococcus aureus. Antimicrob Agents Chemother 58:3599–3609

    Article  PubMed  PubMed Central  Google Scholar 

  24. DiRusso CC, Black PN, Weimar JD (1999) Molecular inroads into the regulation and metabolism of fatty acids, lessons from bacteria. Prog Lipid Res 38:129–197

    Article  CAS  PubMed  Google Scholar 

  25. Black PN (1990) Characterization of FadL-specific fatty acid binding in Escherichia coli. Biochim Biophys Acta 1046:97–105

    Article  CAS  PubMed  Google Scholar 

  26. Van den Berg B (2005) The FadL family: unusual transporters for unusual substrates. Curr Opin Struct Biol 15:401–407

    Article  PubMed  Google Scholar 

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Acknowledgements

Part of the work described herein was initially supported by Award Number SC1 GM084708 from the National Institute of General Medical Sciences (NIGMS) of the NIH. D. Sanabria thanks the National Institute of General Medical Sciences of the National Institutes of Health for an Institutional Development Award (IDeA) Grant (# P20GM103475). N. Montano and C. Morales acknowledge the support of the UPR RISE program (Grant No. 5R25GM061151-15) for graduate fellowships. We thank William O. Marrero for technical assistance. We are in debt to Dr. Mikhail Y. Golovko and Svetlana A. Golovko of the COBRE Mass Spec Core Facility at the Department of Basic Sciences of the University of North Dakota for the high-resolution mass spectral data.

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Authors and Affiliations

  1. Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, 00931-3346, San Juan, PR, USA

    Néstor M. Carballeira, Nashbly Montano & Christian Morales

  2. Faculty of Science and Technology, Inter American University of Puerto Rico, Metropolitan Campus, PO Box 191293, 00919, San Juan, PR, USA

    Joseph Mooney, Xiomara Torres, Dakeishla Díaz & David J. Sanabria-Rios

Authors
  1. Néstor M. Carballeira
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  2. Nashbly Montano
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  3. Christian Morales
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  4. Joseph Mooney
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  5. Xiomara Torres
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  6. Dakeishla Díaz
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  7. David J. Sanabria-Rios
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Correspondence to Néstor M. Carballeira.

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Carballeira, N.M., Montano, N., Morales, C. et al. 2-Methoxylated FA Display Unusual Antibacterial Activity Towards Clinical Isolates of Methicillin-Resistant Staphylococcus aureus (CIMRSA) and Escherichia coli . Lipids 52, 535–548 (2017). https://doi.org/10.1007/s11745-017-4262-1

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