Gausemycin Antibiotic Family Acts via Ca2+-Dependent Membrane Targeting.

We report the molecular mechanism of action of gausemycins and the isolation of new members of the family, gausemycins C (1c), D (1d), E (1e), and F (1f), the minor components of the mixture. To elucidate the mechanism of action of gausemycins, we investigated the antimicrobial activity of the most active compounds, gausemycins A and B, in the presence of Ca2+, other metal ions, and phosphate. Gausemycins require a significantly higher Ca2+ concentration for maximum activity than daptomycin but lower than that required for malacidine and cadasides. Species-specific antimicrobial activity was found upon testing against a wide panel of Gram-positive bacteria. Membranoactivity of gausemycins was demonstrated upon their interactions with model lipid bilayers and micelles. The pore-forming ability was found to be dramatically dependent on the Ca2+ concentration and the membrane lipid composition. An NMR study of gausemycin B in zwitterionic and anionic micelles suggested the putative structure of the gausemycin/membrane complex and revealed the binding of Ca2+ by the macrocyclic domain of the antibiotic.

Random Copolymers of Styrene with Pendant Fluorophore Moieties: Synthesis and Applications as Fluorescence Sensors for Nitroaromatics.

Five random copolymers comprising styrene and styrene with pendant fluorophore moieties, namely pyrene, naphthalene, phenanthrene, and triphenylamine, in molar ratios of 10:1, were synthesized and employed as fluorescent sensors. Their photophysical properties were investigated using absorption and emission spectral analyses in dichloromethane solution and in solid state. All copolymers possessed relative quantum yields up to 0.3 in solution and absolute quantum yields up to 0.93 in solid state, depending on their fluorophore components. Fluorescence studies showed that the emission of these copolymers is highly sensitive towards various nitroaromatic compounds, both in solution and in the vapor phase. The detection limits of these fluorophores for nitroaromatic compounds in dichloromethane solution proved to be in the range of 10-6 to 10-7 mol/L. The sensor materials for new hand-made sniffers based on these fluorophores were prepared by electrospinning and applied for the reliable detection of nitrobenzene vapors at 1 ppm in less than 5 min.

Bicyclic Isoxazoline Derivatives: Synthesis and Evaluation of Biological Activity.

The application of non-planar scaffolds in drug design allows for the enlargement of the chemical space, and for the construction of molecules that have more effective target-ligand interactions or are less prone to the development of resistance. Among the works of the last decade, a literature search revealed spirothiazamenthane, which has served as a lead in the development of derivatives active against resistant viral strains. In this work, we studied the novel molecular scaffold, which resembles spirothiazamenthane, but combines isoxazoline as a heterocycle and cyclooctane ring as a hydrophobic part of the structure. The synthesis of new 3-nitro- and 3-aminoisoxazolines containing spiro-fused or 1,2-annelated cyclooctane fragments was achieved by employing 1,3-dipolar cycloaddition of 3-nitro-4,5-dihydroisoxazol-4-ol 2-oxide or tetranitromethane-derived alkyl nitronates with non-activated alkenes. A series of spiro-sulfonamides was obtained by the reaction of 3-aminoisoxazoline containing a spiro-fused cyclooctane residue with sulfonyl chlorides. Preliminary screening of the compounds for antiviral, antibacterial, antifungal and antiproliferative properties in vitro revealed 1-oxa-2-azaspiro[4.7]dodec-2-en-3-amine and 3a,4,5,6,7,8,9,9a-octahydrocycloocta[d]isoxazol-3-amine with activity against the influenza A/Puerto Rico/8/34 (H1N1) virus in the submicromolar range, and high values of selectivity index. Further study of the mechanism of the antiviral action of these compounds, and the synthesis of their analogues, is likely to identify new agents against resistant viral strains.

Gausemycins†A,B: Cyclic Lipoglycopeptides from Streptomyces sp.*.

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated. The compounds are cyclic peptides with a unique peptide core and several remarkable structural features, including unusual positions of d-amino acids, lack of the Ca2+ -binding Asp-X-Asp-Gly (DXDG) motif, tyrosine glycosylation with arabinose, presence of 2-amino-4-hydroxy-4-phenylbutyric acid (Ahpb) and chlorinated kynurenine (ClKyn), and N-acylation of the ornithine side chain. Gausemycins have pronounced activity against Gram-positive bacteria. Mechanistic studies highlight significant differences compared to known glyco- and lipopeptides. Gausemycins exhibit only slight Ca2+ -dependence of activity and induce no pore formation at low concentrations. Moreover, there is no detectable accumulation of cell wall biosynthesis precursors under treatment with gausemycins.

A Novel Lipopeptaibol Emericellipsin A with Antimicrobial and Antitumor Activity Produced by the Extremophilic Fungus Emericellopsis alkalina.

Soil fungi are known to contain a rich variety of defense metabolites that allow them to compete with other organisms (fungi, bacteria, nematodes, and insects) and help them occupy more preferential areas at the expense of effective antagonism. These compounds possess antibiotic activity towards a wide range of other microbes, particularly fungi that belong to different taxonomical units. These compounds include peptaibols, which are non-ribosomal synthesized polypeptides containing non-standard amino acid residues (alpha-aminoisobutyric acid mandatory) and some posttranslational modifications. We isolated a novel antibiotic peptide from the culture medium of Emericellopsis alkalina, an alkalophilic strain. This peptide, called emericellipsin A, exhibited a strong antifungal effect against the yeast Candida albicans, the mold fungus Aspergillus niger, and human pathogen clinical isolates. It also exhibited antimicrobial activity against some Gram-positive and Gram-negative bacteria. Additionally, emericellipsin A showed a significant cytotoxic effect and was highly active against Hep G2 and HeLa tumor cell lines. We used NMR spectroscopy to reveal that this peptaibol is nine amino acid residues long and contains non-standard amino acids. The mode of molecular action of emericellipsin A is most likely associated with its effects on the membranes of cells. Emericellipsin A is rather short peptaibol and could be useful for the development of antifungal, antibacterial, or anti-tumor remedies.

Detection of nitroaromatic explosives by new D-π-A sensing fluorophores on the basis of the pyrimidine scaffold.

A series of D-π-A- type dyes based on pyrimidines, bearing various thiophene linkers, have been studied as sensing fluorophores. Fluorescence studies have demonstrated that the emission of all derivatives is sensitive to the presence of nitroaromatic explosives, such as 2,4,6-trinitrophenol (PA), 2,4,6-trinitrotoluene (TNT), and 2,4-dinitrotoluene (DNT), in their acetonitrile solutions. The detection limits of fluorophores to PA, TNT, and DNT proved to be in the range from 5.83 × 10(-6) to 2.38 × 10(-7) mol/L, 1.70 × 10(-4) to 8.40 × 10(-6) mol/L, and 8.39 × 10(-5) to 6.87 × 10(-6) mol/L, respectively. The theoretical investigation into the quenching mechanism in the presence of fluorophore has been performed. All compounds have shown a good efficiency as sensor materials when tested as elements of the original device «Nitroscan¼ for detecting nitro-containing explosives in vapor phase (Plant "Promautomatika", Ekaterinburg, Russia). Graphical Abstract ᅟ.

Sensing of Antibiotic-Bacteria Interactions.

Sensing of antibiotic-bacteria interactions is an important area of research that has gained significant attention in recent years. Antibiotic resistance is a major public health concern, and it is essential to develop new strategies for detecting and monitoring bacterial responses to antibiotics in order to maintain effective antibiotic development and antibacterial treatment. This review summarizes recent advances in sensing strategies for antibiotic-bacteria interactions, which are divided into two main parts: studies on the mechanism of action for sensitive bacteria and interrogation of the defense mechanisms for resistant ones. In conclusion, this review provides an overview of the present research landscape concerning antibiotic-bacteria interactions, emphasizing the potential for method adaptation and the integration of machine learning techniques in data analysis, which could potentially lead to a transformative impact on mechanistic studies within the field.

Modern Trends in Natural Antibiotic Discovery.

Natural scaffolds remain an important basis for drug development. Therefore, approaches to natural bioactive compound discovery attract significant attention. In this account, we summarize modern and emerging trends in the screening and identification of natural antibiotics. The methods are divided into three large groups: approaches based on microbiology, chemistry, and molecular biology. The scientific potential of the methods is illustrated with the most prominent and recent results.

Antibiotics from Insect-Associated Actinobacteria.

Actinobacteria are involved into multilateral relationships between insects, their food sources, infectious agents, etc. Antibiotics and related natural products play an essential role in such systems. The literature from the January 2016-August 2022 period devoted to insect-associated actinomycetes with antagonistic and/or enzyme-inhibiting activity was selected. Recent progress in multidisciplinary studies of insect-actinobacterial interactions mediated by antibiotics is summarized and discussed.

Identification of isocyclosporins by collision-induced dissociation of doubly protonated species.

Nonribosomal cyclopeptide cyclosporin A (CsA), produced by fungus Tolypocladium inflatum, is an extremely important immunosuppressive drug used in organ transplantations and for therapy of autoimmune diseases. Here we report for the first time production of CsA, along with related cyclosporins B and C, by Tolypocladium inflatum strains of marine origin (White Sea). Cyclosporins A-C contain an unusual amino acid, (4R)-4-((E)-2-butenyl)-4,N-dimethyl-l-threonine (MeBmt), and are prone to isomerization to non-active isocyclosporin by N→O acyl shift of valine connected to MeBmt in acidic conditions. CsA and isoCsA are not distinguishable in MS analysis of [M+H]+ ions due to rapid [CsA + H]+→[isoCsA + H]+ conversion. We found that the N→O acyl shift is completely suppressed in cyclosporine [M+2H]2+ ions, and their collision-induced dissociation (CID) can be used for rapid and unambiguous analysis of cyclosporins and isocylosporins. Fragmentation patterns of [CsA+2H]2+ and [isoCsA+2H]2+ ions were analyzed and explained. The developed approach could be useful for MS analysis of other peptides containing ß-hydroxy-α-amino acids.

Chemical Ecology of Streptomyces albidoflavus Strain A10 Associated with Carpenter Ant Camponotus vagus.

Antibiotics produced by symbiotic microorganisms were previously shown to be of crucial importance for ecological communities, including ants. Previous works on ant-actinobacteria symbiosis are mainly focused on farming ants, which use antifungal microbial secondary metabolites to control pathogens in their fungal gardens. In this work, we studied microorganisms associated with carpenter ant Camponotus vagus. Pronounced antifungal activity of isolated actinobacteria strain A10 was found to be facilitated by biosynthesis of the antimycin A complex, consisting of small hydrophobic depsipeptides with high antimicrobial and cytotoxic activity. The actinomycete strain A10 was identified as Streptomyces albidoflavus. We studied the antagonistic activity of strain A10 against several entomopathogenic microorganisms. The antifungal activity of this strain potentially indicates a defensive symbiosis with the host ant, producing antimycins to protect carpenter ants against infections. The nature of this ant-microbe association however remains to be established.