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
^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.
^Mor, A. Peptide-based antibiotics: A potential answer to raging antimicrobial resistance. Drug Develop. Res. (2000) 50: 440–447.
^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.
PMID10390813.
S2CID35677695.
^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.
PMID15036865.
^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.
PMID17256853.
^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.
PMID16080719.
S2CID20942103.
^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.
^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.
^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.
PMID10702631.