The Spectrum of Design Solutions for Improving the Activity-Selectivity Product of Peptide Antibiotics against Multidrug-Resistant Bacteria and Prostate Cancer PC-3 Cells.

The link between the antimicrobial and anticancer activity of peptides has long been studied, and the number of peptides identified with both activities has recently increased considerably. In this work, we hypothesized that designed peptides with a wide spectrum of selective antimicrobial activity will also have anticancer activity, and tested this hypothesis with newly designed peptides. The spectrum of peptides, used as partial or full design templates, ranged from cell-penetrating peptides and putative bacteriocin to those from the simplest animals (placozoans) and the Chordata phylum (anurans).

UPLC-MS/MS Phytochemical Analysis of Two Croatian Species and Their Biological Activity.

Aqueous extracts of two species wild growing in Croatia- (CC) and (CS)-have been assessed with UPLC-MS/MS, showing 43 different phytochemicals, with flavonol glycosides: myricetin-3-hexoside and myricetin-rhamnoside, predominate ones in CC and myricetin-3-hexoside in CS. Antioxidant potential tested with the FRAP method showed no difference between CS and CC aqueous extracts, while higher phenolic content of CC comparing to CS, determined with a Folin-Cicolateu reagent correlated to its higher antioxidant capacity observed by the DPPH method. Both extracts were assessed for antimicrobial activity, using disc-diffusion and broth microdilution assays, targeting the opportunistic pathogens, associated with food poisoning, urinary, respiratory tract, blood stream and wound infections in humans.

Confocal Microscopy Confirmed that in Phosphatidylcholine Giant Unilamellar Vesicles with very High Cholesterol Content Pure Cholesterol Bilayer Domains Form.

The cholesterol (Chol) content in the fiber cell plasma membranes of the eye lens is extremely high, exceeding the solubility threshold in the lenses of old humans. This high Chol content forms pure Chol bilayer domains (CBDs) and Chol crystals in model membranes and membranes formed from the total lipid extracts from human lenses. CBDs have been detected using electron paramagnetic resonance (EPR) spin-labeling approaches.

Halogenated boroxine dipotassium trioxohydroxytetrafluorotriborate K[BOFOH] inhibits emerging multidrug-resistant and β-lactamase-producing opportunistic pathogens.

Halogenated boroxine dipotassium trioxohydroxytetrafluorotriborate, K[BOFOH] (boroxine) was previously shown to be very effective in inhibition of several carcinoma cell lines, including the skin cancer. Here, we investigated its antimicrobial potential by targeting the multidrug-resistant opportunistic pathogens associated with skin and wound infections. The antimicrobial testing against eleven bacterial and four fungal species revealed good activity of boroxine against pathogenic filamentous fungi and (MIC 64 and 128 µg/ml), and a moderate bioactivity against the yeast (MIC 512 µg/ml).

Designed peptide with a flexible central motif from ranatuerins adapts its conformation to bacterial membranes.

The long-standing goal in the field of peptide antibiotics has been to design lead compounds that have a wide spectrum of excellent antibacterial activity but are nontoxic to human cells. Gram-negative and Gram-positive bacteria have very different membranes, which are additionally modified in some drug-resistant species, presenting a challenge for the design of a single membrane-active peptide able to adapt its conformation to various physical properties of membrane microenvironments. In this paper, we describe how a peptide sequence can be constructed starting from an adaptable dynamic turn tandem motif in a central location.

Antibacterial Activity Affected by the Conformational Flexibility in Glycine-Lysine Based α-Helical Antimicrobial Peptides.

Antimicrobial peptides often show broad-spectrum activity due to a mechanism based on bacterial membrane disruption, which also reduces development of permanent resistance, a desirable characteristic in view of the escalating multidrug resistance problem. Host cell toxicity however requires design of artificial variants of natural AMPs to increase selectivity and reduce side effects. Kiadins were designed using rules obtained from natural peptides active against E.

PGLa-H tandem-repeat peptides active against multidrug resistant clinical bacterial isolates.

Antimicrobial peptides (AMPs) are promising candidates for new antibiotic classes but often display an unacceptably high toxicity towards human cells. A naturally produced C-terminal fragment of PGLa, named PGLa-H, has been reported to have a very low haemolytic activity while maintaining a moderate antibacterial activity. A sequential tandem repeat of this fragment, diPGLa-H, was designed, as well as an analogue with a Val to Gly substitution at a key position.

Selective antimicrobial activity and mode of action of adepantins, glycine-rich peptide antibiotics based on anuran antimicrobial peptide sequences.

A challenge when designing membrane-active peptide antibiotics with therapeutic potential is how to ensure a useful antibacterial activity whilst avoiding unacceptable cytotoxicity for host cells. Understanding their mode of interaction with membranes and the reasons underlying their ability to distinguish between bacterial and eukaryotic cytoplasmic cells is crucial for any rational attempt to improve this selectivity. We have approached this problem by analysing natural helical antimicrobial peptides of anuran origin, using a structure-activity database to determine an antimicrobial selectivity index (SI) relating the minimal inhibitory concentration against Escherichia coli to the haemolytic activity (SI=HC(50)/MIC).

Knowledge-based computational methods for identifying or designing novel, non-homologous antimicrobial peptides.

We describe computational approaches for identifying promising lead candidates for the development of peptide antibiotics, in the context of quantitative structure-activity relationships (QSAR) studies for this type of molecule. A first approach deals with predicting the selectivity properties of generated antimicrobial peptide sequences in terms of measured therapeutic indices (TI) for known antimicrobial peptides (AMPs). Based on a training set of anuran AMPs, the concept of sequence moments was used to construct algorithms that could predict TIs for a second test set of natural AMPs and could also predict the effect of point mutations on TI values.

Computational design of highly selective antimicrobial peptides.

We have created a structure-selectivity database (AMPad) of frog-derived, helical antimicrobial peptides (AMPs), in which the selectivity was determined as a therapeutic index (TI), and then used the novel concept of sequence moments to study the lengthwise asymmetry of physicochemical peptide properties. We found that the cosine of the angle between two sequence moments obtained with different hydrophobicity scales, defined as the D-descriptor, identifies highly selective peptide antibiotics. We could then use this descriptor to predict TI changes after point mutations in known AMPs, and to aid the prediction of TI for de novo designed AMPs.