The susceptibility of Candida albicans to several fatty acids and their 1-monoglycerides was tested with a short inactivation time, and ultrathin sections were studied by transmission electron microscopy (TEM) after treatment with capric acid. The results show that capric acid, a 10-carbon saturated fatty acid, causes the fastest and most effective killing of all three strains of C. albicans tested, leaving the cytoplasm disorganized and shrunken because of a disrupted or disintegrated plasma membrane. Lauric acid, a 12-carbon saturated fatty acid, was the most active at lower concentrations and after a longer incubation time.
The susceptibilities of three Gram-positive cocci to medium-chain saturated and long-chain unsaturated fatty acids and their one-monoglycerides were studied. The bacteria were incubated with equal volumes of lipid solutions for 10 min. Lauric acid, palmitoleic acid and monocaprin reduced the number of CFU by 6.0 log10 or greater at 5 mM concentration for streptococci of group A (GAS) and group B (GBS). When further compared at lower concentrations and after longer incubation time monocaprin proved to be the most active. Capric acid showed the highest activity against Staphylococcus aureus at 10 mM. However, at lower concentrations monocaprin was the only lipid that showed significant activity against S. aureus. The mode of action of monocaprin against GBS was studied by a novel two-color fluorescent assay of bacterial viability and by electron microscopy. The results indicate that the bacteria are killed by disintegration of the cell membrane by the lipid, leaving the bacterial cell wall intact. The highly lethal effect of monocaprin indicates that this lipid might be useful as a microbicidal agent for prevention and treatment of infections caused by these bacteria.
There is an abundance of antimicrobial peptides in cystic fibrosis (CF) lungs. Despite this, individuals with CF are susceptible to microbial colonization and infection. In this study, we investigated the antimicrobial response within the CF lung, focusing on the human cathelicidin LL-37. We demonstrate the presence of the LL-37 precursor, human cathelicidin precursor protein designated 18-kDa cationic antimicrobial protein, in the CF lung along with evidence that it is processed to active LL-37 by proteinase-3. We demonstrate that despite supranormal levels of LL-37, the lung fluid from CF patients exhibits no demonstrable antimicrobial activity. Furthermore Pseudomonas killing by physiological concentrations of exogenous LL-37 is inhibited by CF bronchoalveolar lavage (BAL) fluid due to proteolytic degradation of LL-37 by neutrophil elastase and cathepsin D. The endogenous LL-37 in CF BAL fluid is protected from this proteolysis by interactions with glycosaminoglycans, but while this protects LL-37 from proteolysis it results in inactivation of LL-37 antimicrobial activity. By digesting glycosaminoglycans in CF BAL fluid, endogenous LL-37 is liberated and the antimicrobial properties of CF BAL fluid restored. High sodium concentrations also liberate LL-37 in CF BAL fluid in vitro. This is also seen in vivo in CF sputum where LL-37 is complexed to glycosaminoglycans but is liberated following nebulized hypertonic saline resulting in increased antimicrobial effect. These data suggest glycosaminoglycan–LL-37 complexes to be potential therapeutic targets. Factors that disrupt glycosaminoglycan–LL-37 aggregates promote the antimicrobial effects of LL-37 with the caveat that concomitant administration of antiproteases may be needed to protect the now liberated LL-37 from proteolytic cleavage.
The antichlamydial effects of several fatty acids and monoglycerides were studied by incubating Chlamydia trachomatis bacteria with equal volumes of lipid solutions for 10 min and measuring the reduction in infectivity titer compared with that in a control solution without lipid. Caprylic acid (8:0), monocaprylin (8:0), monolaurin (12:0), myristic acid (14:0), palmitoleic acid (16:1), monopalmitolein (16:1), oleic acid (18:1), and monoolein (18:1) at concentrations of 20 mM (final concentration, 10 mM) had negligible effects on C. trachomatis. In contrast, lauric acid (12:0), capric acid (10:0), and monocaprin (10:0) caused a greater than 10,000-fold (>4-log10) reduction in the infectivity titer. When the fatty acids and monoglycerides were further compared at lower concentrations and with shorter exposure times, lauric acid was more active than capric acid and monocaprin was the most active, causing a greater than 100,000-fold (>5-log10) inactivation of C. trachomatis at a concentration of 5 mM for 5 min. The high levels of activity of capric and lauric acids and particularly that of monocaprin are notable and suggest that these lipids have specific antichlamydial effects. The mode of action of monocaprin was further studied by removal of the lipid by centrifugation before inoculation ofChlamydia onto host cells and by electron microscopy. The results indicate that the bacteria are killed by the lipid, possibly by disrupting the membrane(s) of the elementary bodies. A 50% effective concentration of 30 μg/ml was found by incubation of Chlamydia with monocaprin for 2 h. The rapid inactivation of large numbers of C. trachomatis organisms by monocaprin suggests that it may be useful as a microbicidal agent for the prevention of the sexual transmission of C. trachomatis.
Vernix caseosa is a white cream-like substance that covers the skin of the foetus and the newborn baby. Recently, we discovered antimicrobial peptides/proteins such as LL-37 in vernix, suggesting host defence functions of vernix. In a proteomic approach, we have continued to characterize proteins in vernix and have identified 20 proteins, plus additional variant forms. The novel proteins identified, considered to be involved in host defence, are cystatin A, UGRP-1, and calgranulin A, B and C. These proteins add protective functions to vernix such as antifungal activity, opsonizing capacity, protease inhibition and parasite inactivation. The composition of the lipids in vernix has also been characterized and among these compounds the free fatty acids were found to exhibit antimicrobial activity. Interestingly, the vernix lipids enhance the antimicrobial activity of LL-37 in vitro, indicating interactions between lipids and antimicrobial peptides in vernix. In conclusion, vernix is a balanced cream of compounds involved in host defence, protecting the foetus and newborn against infection.
Of 11 fatty acids and monoglycerides tested against Campylobacter jejuni, the 1-monoglyceride of capric acid (monocaprin) was the most active in killing the bacterium. Various monocaprin-in-water emulsions were prepared which were stable after storage at room temperature for many months and which retained their microbicidal activity. A procedure was developed to manufacture up to 500 ml of 200 mM preconcentrated emulsions of monocaprin in tap water. The concentrates were clear and remained stable for at least 12 months. They were active against C. jejuni upon 160-to 200-fold dilution in tap water and caused a >6-to 7-log 10 reduction in viable bacterial count in 1 min at room temperature. The addition of 0.8% Tween 40 to the concentrates as an emulsifying agent did not change the microbicidal activity. Emulsions of monocaprin killed a variety of Campylobacter isolates from humans and poultry and also killed strains of Campylobacter coli and Campylobacter lari, indicating a broad anticampylobacter activity. Emulsions of 1.25 mM monocaprin in citrate-lactate buffer at pH 4 to 5 caused a >6-to 7-log 10 reduction in viable bacterial counts of Salmonella spp. and Escherichia coli in 10 min. C. jejuni was also more susceptible to monocaprin emulsions at low pH. The addition of 5 and 10 mM monocaprin emulsions to Campylobacter-spiked chicken feed significantly reduced the bacterial contamination. These results are discussed in view of the possible utilization of monocaprin emulsions in controlling the spread of food-borne bacteria from poultry to humans.
The epidermal mucus of fish species has been found to contain antimicrobial proteins and peptides, which is of interest in regard to fish immunity. An acidic extract from the epidermal mucus of the Atlantic cod (Gadus morhua) was found to exhibit antimicrobial activity against Bacillus megaterium, Escherichia coli and Candida albicans. This activity varied significantly when salt was added to the antimicrobial assay, and was eliminated by pepsin digestion. No lysozyme activity was detected in the extract. By using weak cationic exchange chromatography together with reversed‐phase chromatography, and monitoring the antimicrobial activity, we have isolated four cationic proteins from the mucus extract. Using N‐terminal and C‐terminal amino acid sequence analysis, together with MS, the antimicrobial proteins were identified as histone H2B (13 565 Da), ribosomal protein L40 (6397 Da), ribosomal protein L36A (12 340 Da) and ribosomal protein L35 (14 215 Da). The broad spectra of antimicrobial activities in the cod mucus and the characterization of four antimicrobial polypeptides suggest that mucus compounds contribute to the innate host defence of cod.
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