Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and ...bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a
model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of
. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.
One strategy to combat antimicrobial resistance is the discovery of new classes of antibiotics. Most antibiotics will at some point interact with the bacterial membrane to either interfere with its ...integrity or to cross it. Reliable and efficient tools for determining the dissociation constant for membrane binding (K
) and the partitioning coefficient between the aqueous- and membrane phases (K
) are therefore important tools for discovering and optimizing antimicrobial hits. Here we demonstrate that microscale thermophoresis (MST) can be used for label-free measurement of K
by utilising the intrinsic fluorescence of tryptophan and thereby removing the need for chromophore labelling. As proof of principle, we have used the method to measure the binding of a set of small cyclic AMPs to large unilamellar vesicles (LUVs) and two types of lipid nanodiscs assembled by styrene maleic acid (SMA) and quaternary ammonium SMA (SMA-QA). The measured K
values correlate well with the corresponding measurements using surface plasmon resonance (SPR), also broadly reflecting the tested AMPs' minimal inhibition concentration (MIC) towards S. aureus and E. coli. We conclude that MST is a promising method for fast and cost-efficient detection of peptide-lipid interactions or mapping of sample conditions in preparation for more advanced studies that rely on expensive sample preparation, labelling and/or instrument time.
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Vitamin D induces the expression of antimicrobial peptides with activity against
Staphylococcus aureus
. Thus, we studied the association between serum 25-hydroxyvitamin D (25(OH)D) and
S. aureus
...nasal colonization and carriage. Nasal swabs, blood samples and clinical data from 2,115 women and 1,674 men, aged 30–87 years, were collected in the Tromsø Staph and Skin Study 2007–08, as part of the population-based sixth Tromsø Study. Multivariate logistic regression analyses were stratified by recognized risk factors for
S. aureus
carriage: sex, age and smoking. In non-smoking men, we observed a 6.6% and 6.7% decrease in the probability of
S. aureus
colonization and carriage, respectively, by each 5 nmol/l increase in serum 25(OH)D concentration (
P
< 0.001 and
P
= 0.001), and serum 25(OH)D > 59 nmol/l and ≥75 nmol/l as thresholds for ~30% and ~50% reduction in
S. aureus
colonization and carriage. In non-smoking men aged 44–60 years, the odds ratio for
S. aureus
colonization was 0.44 (95% confidence interval, 0.28−0.69) in the top tertile of serum 25(OH)D versus the bottom tertile. In women and smokers there were no such associations. Our study supports that serum vitamin D is a determinant of
S. aureus
colonization and carriage.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Polymorphisms of the FA desaturase (FADS) gene cluster have been associated with LDL, HDL, and triglyceride concentrations. Because FADS converts α-linolenic acid (ALA) and linoleic acid into PUFAs, ...we investigated the interaction between different PUFA intakes and the FADS polymorphism rs174547 (T>C) on fasting blood lipid and lipoprotein concentrations. We included 4,635 individuals (60% females, 45–68 years) from the Swedish population-based Malmö Diet and Cancer cohort. Dietary intakes were assessed by a modified diet history method including 7-day registration of cooked meals. The C-allele of rs174547 was associated with lower LDL concentration (P = 0.03). We observed significant interaction between rs174547 and long-chain ω-3 PUFA intakes on LDL (P = 0.01); the C-allele was only associated with lower LDL among individuals in the lowest tertile of long-chain ω-3 PUFA intakes (P < 0.001). In addition, significant interaction was observed between rs174547 and the ratio of ALA and linoleic FA intakes on HDL (P = 0.03). However, no significant associations between the C-allele and HDL were detected within the intake tertiles of the ratio. Our findings suggest that dietary intake levels of different PUFAs modify the associated effect of genetic variation in FADS on LDL and HDL
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Staphylococcus haemolyticus is an emerging cause of nosocomial infections, primarily affecting immunocompromised patients. A comparative genomic analysis was performed on clinical S. haemolyticus ...isolates to investigate their genetic relationship and explore the coding sequences with respect to antimicrobial resistance determinants and putative hospital adaptation.
Whole-genome sequencing was performed on 134 isolates of S. haemolyticus from geographically diverse origins (Belgium, 2; Germany, 10; Japan, 13; Norway, 54; Spain, 2; Switzerland, 43; UK, 9; USA, 1). Each genome was individually assembled. Protein coding sequences (CDSs) were predicted and homologous genes were categorized into three types: Type I, core genes, homologues present in all strains; Type II, unique core genes, homologues shared by only a subgroup of strains; and Type III, unique genes, strain-specific CDSs. The phylogenetic relationship between the isolates was built from variable sites in the form of single nucleotide polymorphisms (SNPs) in the core genome and used to construct a maximum likelihood phylogeny.
SNPs in the genome core regions divided the isolates into one major group of 126 isolates and one minor group of isolates with highly diverse genomes. The major group was further subdivided into seven clades (A-G), of which four (A-D) encompassed isolates only from Europe. Antimicrobial multiresistance was observed in 77.7% of the collection. High levels of homologous recombination were detected in genes involved in adherence, staphylococcal host adaptation and bacterial cell communication.
The presence of several successful and highly resistant clones underlines the adaptive potential of this opportunistic pathogen.
Treatment options for infections caused by antimicrobial-resistant bacteria are rendered ineffective, and drug alternatives are needed-either from new chemical classes or drugs with new modes of ...action. Historically, natural products have been important contributors to drug discovery. In a recent study, the dimeric naphthopyrone lulworthinone produced by an obligate marine fungus in the family
was discovered. The observed potent antibacterial activity against Gram-positive bacteria, including several clinical methicillin-resistant
(MRSA) isolates, prompted this follow-up mode of action investigation. This paper aimed to characterize the antibacterial mode of action (MOA) of lulworthinone by combining in vitro assays, NMR experiments and microscopy. The results point to a MOA targeting the bacterial membrane, leading to improper cell division. Treatment with lulworthinone induced an upregulation of genes responding to cell envelope stress in
. Analysis of the membrane integrity and membrane potential indicated that lulworthinone targets the bacterial membrane without destroying it. This was supported by NMR experiments using artificial lipid bilayers. Fluorescence microscopy revealed that lulworthinone affects cell morphology and impedes the localization of the cell division protein FtsZ. Surface plasmon resonance and dynamic light scattering assays showed that this activity is linked with the compound's ability to form colloidal aggregates. Antibacterial agents acting at cell membranes are of special interest, as the development of bacterial resistance to such compounds is deemed more difficult to occur.
Antimicrobial peptides (AMPs) are generally membrane-active compounds that physically disrupt bacterial membranes. Despite extensive research, the precise mode of action of AMPs is still a topic of ...great debate. This work demonstrates that the initial interaction between the Gram-negative
and AMPs is driven by lipopolysaccharides (LPS) that act as kinetic barriers for the binding of AMPs to the bacterial membrane. A combination of SPR and NMR experiments provide evidence suggesting that cationic AMPs first bind to the negatively charged LPS before reaching a binding place in the lipid bilayer. In the event that the initial LPS-binding is too strong (corresponding to a low dissociation rate), the cationic AMPs cannot effectively get from the LPS to the membrane, and their antimicrobial potency will thus be diminished. On the other hand, the AMPs must also be able to effectively interact with the membrane to exert its activity. The ability of the studied cyclic hexapeptides to bind LPS and to translocate into a lipid membrane is related to the nature of the cationic charge (arginine vs. lysine) and to the distribution of hydrophobicity along the molecule (alternating vs. clumped tryptophan).
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