Biologically relevant surrogates of coumarins: 2-phenyl H-isophosphinoline 2-oxides with antibacterial activity

The present study aims to investigate the in vitro antibacterial activities of several isophosphinoline-2-oxides that can be perceived as combined bio isosteres of coumarins and flavonoids. More specifically, antibacterial activity was evaluated against four bacterial strains, including the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and the Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis by using disk diffusion assay. Notably, isophosphinoline-2-oxide compounds showed promising and highly selective antimicrobial activity against S. aureus.

Difficulties in therapy of aerobic vaginitis and ways to overcome them

Pathological discharge from the genital tract and other signs of discomfort of the external genitalia are a common cause of a visit to the gynecologist. The cause of these disorders in most cases is vulvovaginal infection, accompanied (vaginitis) or not accompanied (vaginosis) by leukocyte reaction. Methods for treating vulvovaginal infection are predominantly local therapy or systemic agents with highly selective antimicrobial activity. Since a significant part of the vaginitis is of mixed polymicrobial origin, treatment should be complex, which determines the possibility of prescribing topical medicines containing several components of a wide spectrum of action. At the same time, the complexity of diagnosis and the time spent on it allow one to talk about the advisability of empirical therapy of vulvovaginitis, accompanied by severe clinical symptoms.

Nisin- and ripcin-derived hybrid lanthipeptides display selective antimicrobial activity against Staphylococcus aureus

Lanthipeptides are (methyl)lanthionine ring-containing ribosomally synthesized and post-translationally modified peptides (RiPPs). Many lanthipeptides show strong antimicrobial activity against bacterial pathogens, including antibiotic-resistant bacterial pathogens. The group of disulfide bond-containing antimicrobial peptides (AMPs) is well known in nature and forms a rich source of templates for the production of novel peptides with corresponding (methyl)lanthionine analogues instead of disulfides. Here, we show that novel macrocyclic lanthipeptides (termed thanacin and ripcin) can be synthesized using the known antimicrobials thanatin and rip-thanatin as templates. Notably, the synthesized nisin(1-20)-ripcin hybrid lanthipeptides (ripcin B-G) showed selective antimicrobial activity against S. aureus, including an antibiotic-resistant MRSA strain. Interestingly, ripcin B-G, which are hybrid peptides of nisin(1-20) and ripcin, respectively, that are each inactive against Gram-negative pathogens, showed substantial antimicrobial activity against the tested Gram-negative pathogens. Moreover, ripcin B-G was highly resistant against the nisin resistance protein (NSR; a protease could cleave nisin and strongly reduce its activity ), opposed to nisin itself. Mode of action studies show that ripcin C exerts its antimicrobial activity against Gram-positive pathogens by binding to the cell wall synthesis precursor lipid II and thereafter arrests cell growth. In addition, ripcin C exerts its antimicrobial activity against Gram-negative pathogens by binding to LPS and the cell wall synthesis precursor lipid II. This study provides an example of converting disulfide bond-based AMPs into (methyl)lanthionine-based macrocyclic hybrid lanthipeptides and can yield antimicrobial peptides with selective antimicrobial activity against S. aureus.

Transcriptome Signatures in Pseudomonas simiae WCS417 Shed Light on Role of Root-Secreted Coumarins in Arabidopsis-Mutualist Communication

Pseudomonas simiae WCS417 is a root-colonizing bacterium with well-established plant-beneficial effects. Upon colonization of Arabidopsis roots, WCS417 evades local root immune responses while triggering an induced systemic resistance (ISR) in the leaves. The early onset of ISR in roots shows similarities with the iron deficiency response, as both responses are associated with the production and secretion of coumarins. Coumarins can mobilize iron from the soil environment and have a selective antimicrobial activity that impacts microbiome assembly in the rhizosphere. Being highly coumarin-tolerant, WCS417 induces the secretion of these phenolic compounds, likely to improve its own niche establishment, while providing growth and immunity benefits for the host in return. To investigate the possible signaling function of coumarins in the mutualistic Arabidopsis-WCS417 interaction, we analyzed the transcriptome of WCS417 growing in root exudates of coumarin-producing Arabidopsis Col-0 and the coumarin-biosynthesis mutant f6′h1. We found that coumarins in F6′H1-dependent root exudates significantly affected the expression of 439 bacterial genes (8% of the bacterial genome). Of those, genes with functions related to transport and metabolism of carbohydrates, amino acids, and nucleotides were induced, whereas genes with functions related to cell motility, the bacterial mobilome, and energy production and conversion were repressed. Strikingly, most genes related to flagellar biosynthesis were down-regulated by F6′H1-dependent root exudates and we found that application of selected coumarins reduces bacterial motility. These findings suggest that coumarins’ function in the rhizosphere as semiochemicals in the communication between the roots and WCS417. Collectively, our results provide important novel leads for future functional analysis of molecular processes in the establishment of plant-mutualist interactions.

Di-anionic self-associating supramolecular amphiphiles (SSAs) as antimicrobial agents against MRSA and Escherichia coli

Amphiphilic agents demonstrate selective antimicrobial activity against MRSA and are shown to form interesting macrocyclic structures in the solid state.

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). We applied custom computational tools to predict amino acid substitutions, conferring the increased product of bacteriostatic activity and selectivity. Experiments confirmed that better overall performance was achieved with respect to that of initial templates. Nine of our synthesized helical peptides had excellent bactericidal activity against both standard and multidrug-resistant bacteria. These peptides were then compared to a known anticancer peptide polybia-MP1, for their ability to kill prostate cancer cells and dermal primary fibroblasts. The therapeutic index was higher for seven of our peptides, and anticancer activity stronger for all of them. In conclusion, the peptides that we designed for selective antimicrobial activity also have promising potential for anticancer applications.

Phytochemical, Cytotoxic, and Antimicrobial Evaluation of the Fruits of Miswak Plant, Salvadora persica L.

Salvadora persica L. (Salvadoraceae) is an evergreen shrub growing in the Middle East, Africa, and Southern Asia. It is traditionally known as “miswak” and used as toothbrushes and for the treatment of toothache, gum diseases, boils, chest infection, gonorrhea, headache, spleen troubles, stomachache, and ulcers. To the best of our knowledge, this is the first study aimed at conducting phytochemical, cytotoxic, and antimicrobial investigations of the fruits (berries) of S. persica collected from the Jazan region of Saudi Arabia. Analysis of the ethanol extract of S. persica fruits using GC-MS showed the presence of six esters (20.71%), seven alkanes (15.47%), tetracosamethyl-cyclododecasiloxane (9.91%), eicosamethyl-cyclodecasiloxane (7.27%), and 1-monolinoleoylglycerol (5.17%). The predominant constituents were acetyl dasycarpidan-1-methanol (10.47%), tetracosamethyl-cyclododecasiloxane (9.91%), eicosamethyl-cyclodecasiloxane (7.27%), and 1-monolinoleoylglycerol (5.17%). The petroleum ether extract of the fruits contained mainly eicosamethyl-cyclodecasiloxane (23.81%), 1-monolinoleoylglycerol (11.78%), (Z,Z,Z)-9,12,15-octadecatrienoic acid ethyl ester derivative (10.56%), and tetracosamethyl-cyclododecasiloxane (9.91%). The cytotoxic properties of the ethanol extract were investigated by MTT assay against the breast MCF7, ovary A2780, and colon HT29 cells. The fruit extract of S. persica was selective against the ovarian and colon cancer cells compared to normal fibroblast cells (MRC5) as it showed IC50 values 17.50, 8.35, and 5.12, against MCF7, A2780, and HT29 cells, respectively. Interestingly, the fruit extract was also found to possess selective antimicrobial activity for Streptococcus mutans isolates with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 3.12 and 6.25 mg/mL, respectively. Interestingly, it was found to be ineffective against other Gram-positive as well as Gram-negative microorganisms. This study provides insight into the bioactive components present in the fruits of the plant that can be utilized for its cytotoxic and antimicrobial properties.