Surfactin
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.110.185
  • InChI=1S/C53H93N7O13/c1-30(2)20-18-16-14-13-15-17-19-21-36-28-43(61)54-37(22-23-44(62)63)47(66)55-38(24-31(3)4)48(67)57-40(26-33(7)8)51(70)60-46(35(11)12)52(71)58-41(29-45(64)65)50(69)56-39(25-32(5)6)49(68)59-42(27-34(9)10)53(72)73-36/h30-42,46H,13-29H2,1-12H3,(H,54,61)(H,55,66)(H,56,69)(H,57,67)(H,58,71)(H,59,68)(H,60,70)(H,62,63)(H,64,65)/t36-,37+,38+,39-,40-,41+,42+,46+/m1/s1
    Key: NJGWOFRZMQRKHT-WGVNQGGSSA-N
  • InChI=1/C53H93N7O13/c1-30(2)20-18-16-14-13-15-17-19-21-36-28-43(61)54-37(22-23-44(62)63)47(66)55-38(24-31(3)4)48(67)57-40(26-33(7)8)51(70)60-46(35(11)12)52(71)58-41(29-45(64)65)50(69)56-39(25-32(5)6)49(68)59-42(27-34(9)10)53(72)73-36/h30-42,46H,13-29H2,1-12H3,(H,54,61)(H,55,66)(H,56,69)(H,57,67)(H,58,71)(H,59,68)(H,60,70)(H,62,63)(H,64,65)/t36-,37+,38+,39-,40-,41+,42+,46+/m1/s1
    Key: NJGWOFRZMQRKHT-WGVNQGGSBQ
  • CC(C)CCCCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1
Properties
C53H93N7O13
Molar mass 1036.3 g/mol
Surface tension:
9.4 × 10−6 M (pH 8.7)[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Identifiers
SymbolN/A
TCDB1.D.11
OPM superfamily163
OPM protein2npv

Surfactin is a cyclic lipopeptide, commonly used as an antibiotic for its capacity as a surfactant.[2] It is an amphiphile capable of withstanding hydrophilic and hydrophobic environments. The Gram-positive bacterial species Bacillus subtilis produces surfactin for its antibiotic effects against competitors.[3] Surfactin showcases antibacterial, antiviral, antifungal, and hemolytic effects.[4]

Structure and Synthesis

The structure consists of a peptide loop of seven amino acids (L-glutamic acid, L-leucine, D-leucine, L-valine, L-aspartic acid, D-leucine, and L-leucine) and a β-hydroxy fatty acid of variable length, thirteen to fifteen carbon atoms long.[5] The glutamic acid and aspartic acid residues give the ring its hydrophilic character, as well as its negative charge. Conversely, the valine residue extends down, facing the fatty acid chain, to form a major hydrophobic domain. Below critical micellar concentrations (CMCs), the fatty acid tail can extend freely into solution, participating in hydrophobic interactions within micelles.[6] This antibiotic is synthesized by a linear nonribosomal peptide synthetase, surfactin synthetase (Q04747). In solution, it has a characteristic "horse saddle" conformation (PDB: 2NPV) that explains its large spectrum of biological activity.[7][8]

Physical properties

Surface tension

Surfactin, like other surfactants, affects the surface tension of liquids in which it is dissolved. It can lower the water's surface tension from 72 mN/m to 27 mN/m at concentrations as low as 20 μM.[9] Surfactin accomplishes this effect by occupying the intermolecular space between water molecules, decreasing the attractive forces between adjacent water molecules, mainly hydrogen bonds, to increase the solution's fluidity. This property makes surfactin and other surfactants useful as detergents and soaps.[10]

Molecular mechanisms

There are three prevailing hypotheses for how surfactin works.[11]

Cation-carrier effect

The cation-carrier effect is characterized by surfactin's ability to drive monovalent and divalent cations through an organic barrier. The two acidic residues aspartate and glutamate form a "claw" to stabilize divalent cations, such as Ca2+ ions used as an assembly template for the formation of micelles. When surfactin penetrates the outer sheet, its fatty acid chain interacts with the acyl chains of the phospholipids, orienting its headgroup toward the phospholipids' polar heads. Attachment of a cation causes the complex to cross the bilipidic layer using flippase enzymes. The headgroup aligns itself with the phospholipids of the inner sheet and the fatty acid chain interacts with the phospholipids acyl chains. The cation is then delivered into the intracellular medium.[12]

Pore-forming effect

The pore-forming (ion channel) effect is characterized by the formation of cationic channels. It requires surfactin to self-associate inside the membrane since it cannot span across the cellular membrane. Under a hypothesis focused on uncharged membranes with minimal activation energy required to cross between inner and outer leaflets, molecular self-assembly would form a channel structure.[11]

Detergent effect

The detergent effect draws on surfactin's ability to insert its fatty acid chain into the phospholipid layer, disorganizing the cell membrane to increase its permeability.[13] Insertion of several surfactin molecules into the membrane can lead to the formation of mixed micelles by self-association and bilayer influenced by fatty chain hydrophobicity ultimately leading to bilayer solubilization.[14]

Biological properties

Antibacterial and antiviral properties

Surfactin is a broad-spectrum antibiotic with detergent-like activity increasing the permeability of cell membranes in all bacteria, regardless of their Gram stain classification.[15] The minimum inhibitory concentration (MIC) of surfactin is between 12-50 μg/ml.[16]

Surfactin is also capable of degrading viral envelope lipids and forming ion channels in the inner capsid with experimental evidence showing inhibition of HIV and HSV. However, surfactin can only degrade viruses when they are outside of host cells. Furthermore, when the environment is packed with proteins and lipids, surfactin faces a buffer effect lowering its antiviral activity.[17]

Toxicity

Surfactin has non-specific cytotoxicity, causing lysis through disruption to the phospholipid bilayer present in all cells. When injected into humans as an intravascular antibiotic at concentrations at or above the LD50 of 40-60 μM, surfactin has hemolytic effects.[18]

References

  1. ↑ Ishigami Y, Osman M, Nakahara H, Sano Y, Ishiguro R, Matsumoto M (July 1995). "Significance of β-sheet formation for micellization and surface adsorption of surfactin". Colloids and Surfaces B: Biointerfaces. 4 (6): 341–348. doi:10.1016/0927-7765(94)01183-6.{{cite journal}}: CS1 maint: overridden setting (link)
  2. ↑ Mor, A. Peptide-based antibiotics: A potential answer to raging antimicrobial resistance. Drug Develop. Res. (2000) 50: 440–447.
  3. ↑ Peypoux F, Bonmatin JM, Wallach J (May 1999). "Recent trends in the biochemistry of surfactin". Applied Microbiology and Biotechnology. 51 (5): 553–63. doi:10.1007/s002530051432. PMID 10390813. S2CID 35677695.
  4. ↑ Singh P, Cameotra SS (March 2004). "Potential applications of microbial surfactants in biomedical sciences". Trends in Biotechnology. 22 (3): 142–6. doi:10.1016/j.tibtech.2004.01.010. PMID 15036865.
  5. ↑ Bonmatin JM, Laprévote O, Peypoux F (September 2003). "Diversity among microbial cyclic lipopeptides: iturins and surfactins. Activity-structure relationships to design new bioactive agents". Combinatorial Chemistry & High Throughput Screening. 6 (6): 541–56. doi:10.2174/138620703106298716. PMID 14529379.
  6. ↑ Grau A, Gómez Fernández JC, Peypoux F, Ortiz A (May 1999). "A study on the interactions of surfactin with phospholipid vesicles". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1418 (2): 307–19. doi:10.1016/S0005-2736(99)00039-5. PMID 10320682.
  7. ↑ Hue N, Serani L, Laprévote O (2001). "Structural investigation of cyclic peptidolipids from Bacillus subtilis by high-energy tandem mass spectrometry". Rapid Communications in Mass Spectrometry. 15 (3): 203–9. Bibcode:2001RCMS...15..203H. doi:10.1002/1097-0231(20010215)15:3<203::AID-RCM212>3.0.CO;2-6. PMID 11180551.
  8. ↑ Tsan P, Volpon L, Besson F, Lancelin JM (February 2007). "Structure and dynamics of surfactin studied by NMR in micellar media". Journal of the American Chemical Society. 129 (7): 1968–77. doi:10.1021/ja066117q. PMID 17256853.
  9. ↑ Yeh MS, Wei YH, Chang JS (2005). "Enhanced production of surfactin from Bacillus subtilis by addition of solid carriers". Biotechnology Progress. 21 (4): 1329–34. doi:10.1021/bp050040c. PMID 16080719. S2CID 20942103.
  10. ↑ Wójtowicz K, Czogalla A, Trombik T, Łukaszewicz M (2021-12-01). "Surfactin cyclic lipopeptides change the plasma membrane composition and lateral organization in mammalian cells". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1863 (12): 183730. doi:10.1016/j.bbamem.2021.183730. ISSN 0005-2736. PMID 34419486.
  11. 1 2 Deleu M, Bouffioux O, Razafindralambo H, Paquot M, Hbid C, Thonart P, Jacques P, Brasseur R (April 2003). "Interaction of Surfactin with Membranes: A Computational Approach". Langmuir. 19 (8): 3377–3385. doi:10.1021/la026543z.
  12. ↑ Heerklotz H, Wieprecht T, Seelig J (April 2004). "Membrane Perturbation by the Lipopeptide Surfactin and Detergents as Studied by Deuterium NMR". The Journal of Physical Chemistry B. 108 (15): 4909–4915. doi:10.1021/jp0371938.
  13. ↑ Kragh-Hansen, U, M Maire, and J Moller. The Mechanism of Detergent Solubilization of Liposomes and Protein-Containing Membranes. Biophys. J. (1998) 75: 2932–2946.
  14. ↑ le Maire M, Champeil P, Moller JV (November 2000). "Interaction of membrane proteins and lipids with solubilizing detergents". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1508 (1–2): 86–111. doi:10.1016/S0304-4157(00)00010-1. PMID 11090820.
  15. ↑ Sudarmono P, Wibisana A, Listriyani LW, Sungkar S (2019-03-10). "Characterization and Synergistic Antimicrobial Evaluation of Lipopeptides from Bacillus amyloliquefaciens Isolated from Oil-Contaminated Soil". International Journal of Microbiology. 2019: e3704198. doi:10.1155/2019/3704198. ISSN 1687-918X. PMC 6431436. PMID 30956662.
  16. ↑ Heerklotz H, Seelig J (September 2001). "Detergent-like action of the antibiotic peptide surfactin on lipid membranes". Biophysical Journal. 81 (3): 1547–54. Bibcode:2001BpJ....81.1547H. doi:10.1016/S0006-3495(01)75808-0. PMC 1301632. PMID 11509367.
  17. ↑ Jung M, Lee S, Kim H (June 2000). "Recent studies on natural products as anti-HIV agents". Current Medicinal Chemistry. 7 (6): 649–61. doi:10.2174/0929867003374822. PMID 10702631.
  18. ↑ Dehghan-Noudeh G, Housaindokht M, Sedigeh Fazly Bazzar B (June 2005). "Isolation, Characterization, and Investigation of Surface and Hemolytic Activities of a Lipopeptide Biosurfactant Produced by Bacillus subtilis ATCC 6633". The Journal of Microbiology. The Microbiological Society of Korea. 43 (3): 272–276. PMID 15995646.
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