Antibacterial activity of peptides homologous to a loop region in human lactoferrin

Odell, Edward; Sarra, R.; Foxworthy, Morwenna; Chapple, Daniel S.; Evans, Robert W.

doi:10.1016/0014-5793(96)00168-8

Cited by 79 publications

(69 citation statements)

References 30 publications

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“…The smaller dLPA molecule may be able to more readily gain access to the binding site, whereas the larger LPS molecule would be unable to interact with the site. Binding of LPS (or dLPA) to many LPS-binding proteins is via interaction of the phosphate groups on the LPA with specific positively charged residues within the LPS-binding protein (1,3,14,17,20,21,25,26,28,31,35,39,41). C1INH has one Arg (at position 18) and 3 Lys residues (at positions 22, 30, and 55) within the amino-terminal domain.…”

Section: Discussionmentioning

confidence: 99%

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

Scafidi

et al. 2004

Infect Immun

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C1 inhibitor (C1INH) prevents endotoxin shock in mice via a direct interaction with lipopolysaccharide (LPS). This interaction requires the heavily glycosylated amino-terminal domain of C1INH. C1INH in which N-linked carbohydrate was removed by using N-glycosidase F was markedly less effective in protecting mice from LPS-induced lethal septic shock. N-deglycosylated C1INH also failed to suppress fluorescein isothiocyanate (FITC)-LPS binding to and LPS-induced tumor necrosis factor alpha mRNA expression by the murine macrophage-like cell line, RAW 264.7, and cells in human whole blood. In an enzyme linked immunosorbent assay, the N-deglycosylated C1INH bound to LPS very poorly. In addition, C1INH was shown to bind to diphosphoryl lipid A (dLPA) but only weakly to monophosphoryl lipid A (mLPA). As with intact LPS, binding of N-deglycosylated C1INH to dLPA and mLPA was diminished in comparison with the native protein.Removal of O-linked carbohydrate had no effect on any of these activities. Neither detoxified LPS, dLPA, nor mLPA had any effect on the rate or extent of C1INH complex formation with C1s or on cleavage of the reactive center loop by trypsin. These data demonstrate that N-linked glycosylation of C1INH is essential to mediate its interaction with the LPA moiety of LPS and to protect mice from endotoxin shock.Septic shock caused by gram-negative bacteria is due primarily to endotoxin lipopolysaccharide (LPS), which is a complex glycolipid found in the outer membrane of all gram-negative bacteria (6). Treatment of gram-negative bacterial infections would be greatly aided by substances that can effectively block production of inflammatory mediators from LPS-induced mononuclear phagocytes. Administration of LPS to humans or experimental animals results in many of the physiological changes observed during gram-negative bacterial infection, including fever, hypotension, hypoglycemia, disseminated intravascular coagulation, and shock (5). LPS is composed of two chemically dissimilar structural regions: the hydrophilic repeating polysaccharide of the core and O-antigen structures and a hydrophobic domain known as lipid A (LPA) (40). LPA is the toxic principle of gram-negative bacterial LPS and has full endotoxin activity (15,38). Virtually all LPS-induced biological responses are LPA dependent (33). Therefore, recognition of LPA by cells must be the initial step in LPSinduced cellular responses. The general chemical structure of LPA from diverse gram-negative bacteria is highly conserved (40). LPA has the biological function to induce nuclear factor-B activation in monocytes (24) and the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL-1) from macrophages (2, 16). The acute-phase reactant LPS binding-protein (LBP) binds to the LPA moiety with high affinity and facilitates the transfer of LPS to CD14 (38,40,44). LPA contains the binding domain recognized by LPS-binding proteins, but the polysaccharide O chain and oligosaccharide core structure of endotoxin ...

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Section: Discussionmentioning

confidence: 99%

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

Scafidi

et al. 2004

Infect Immun

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“…Finally, dose-response studies revealed that hLF(1-11) was considerably (P Ͻ 0.05) more efficient than hLF (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) in increasing the membrane permeability of bacteria (Fig. 2).…”

Section: Fig 2 Killing Of Antibiotic-resistant S Aureus (A) L Momentioning

confidence: 95%

“…was applied instead of hLF or hLF Ϫ3N . Synthetic peptides corresponding to residues 1 to 11 of hLF (GRRRRSVQWCA, 1,494 Da), referred to below as hLF (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), and fragments thereof and a peptide corresponding to residues 21 to 31 of hLF (FQWQRN MRKVR, 1,567 Da), referred to below as hLF (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), were prepared and purified as described previously (4). The purity of the synthetic peptides usually exceeded 88%, as determined by reverse-phase high-performance liquid chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…Next, we compared the bactericidal activities of hLF (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), which includes the second cationic domain of hLF and is known to display bactericidal activity (22), and hLF(1-11) against antibiotic-resistant S. aureus, L. monocytogenes, K. pneumoniae, and E. coli. The results revealed that hLF(1-11) is at least 10 times more (P Ͻ 0.05) efficient than hLF(21-31) (Fig.…”

Section: ؊3nmentioning

confidence: 99%

“…However, since iron-saturated hLF is also able to kill certain bacteria (7), mechanisms other than iron depletion apparently are involved in the antibacterial activity of LF. Recent studies have indicated that peptides obtained after enzymatic hydrolysis of hLF (1,22,37) and bovine LF (bLF) (5,12,30) are much more effective in killing bacteria than is the intact protein. Amino acid sequence analysis revealed that these antimicrobial peptides comprised (parts of) the N-terminal residues 1 to 47 of hLF (1,37) or 1 to 48 of bLF (5,12).…”

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confidence: 99%

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Human Lactoferrin and Peptides Derived from Its N Terminus Are Highly Effective against Infections with Antibiotic-Resistant Bacteria

et al. 2001

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Since human lactoferrin (hLF) binds to bacterial products through its highly positively charged N terminus, we investigated which of the two cationic domains is involved in its bactericidal activity. The results revealed that hLF lacking the first three residues (hLF ؊3N ) was less efficient than hLF in killing of antibiotic-resistant Staphylococcus aureus, Listeria monocytogenes, and Klebsiella pneumoniae. Both hLF preparations failed to kill Escherichia coli O54. In addition, hLF ؊3N was less effective than hLF in reducing the number of viable bacteria in mice infected with antibiotic-resistant S. aureus and K. pneumoniae. Studies with synthetic peptides corresponding to the first 11 N-terminal amino acids, designated hLF(1-11), and fragments thereof demonstrated that peptides lacking the first three N-terminal residues are less effective than hLF(1-11) in killing of bacteria. Furthermore, a peptide corresponding to residues 21 to 31, which comprises the second cationic domain, was less effective than hLF(1-11) in killing of bacteria in vitro and in mice having an infection with antibioticresistant S. aureus or K. pneumoniae. Using fluorescent probes, we found that bactericidal hLF peptides, but not nonbactericidal peptides, caused an increase of the membrane permeability. In addition, hLF killed the various bacteria, most probably by inducing intracellular changes in these bacteria without affecting the membrane permeability. Together, hLF and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant S. aureus and K. pneumoniae, and the first two arginines play an essential role in this activity.

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Food‐derived multifunctional bioactive proteins and peptides

Agyei

Potumarthi

Danquah

2015

Biotechnology of Bioactive Compounds

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Antibacterial activity of peptides homologous to a loop region in human lactoferrin

Cited by 79 publications

References 30 publications

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

Human Lactoferrin and Peptides Derived from Its N Terminus Are Highly Effective against Infections with Antibiotic-Resistant Bacteria

Food‐derived multifunctional bioactive proteins and peptides

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