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The peptide albicidin represents a highly promising lead structure which is a first-in-class antibiotic with remarkable potency against gram-negative bacteria. Past efforts in the synthesis of albicidin analogs focused on increasing hydrophilicity, broadening of the antibacterial profile and overcoming resistance. Herein, we present synthetic albicidin derivatives with variations in the N-terminal building block and characterize their antibacterial activity and DNA gyrase inhibition. Furthermore, we show that the N‑terminus of albicidin greatly affects binding to the resistance factor AlbAL. This transcription regulator senses albicidin and triggers the biosynthesis of the binding protein AlbAS, thus reducing the free concentration of the antibiotic. Here we demonstrate uncoupling of the binding event from transcription activation for some derivatives, and even a few derivatives seemed insensitive to sequestration by AlbA. This approach could be a strategy to develop albicidin analogs escaping AlbA resistance., (© 2025 Wiley‐VCH GmbH.) more...

Fast and reliable identification of bacteria directly in clinical samples is a critical factor in clinical microbiological diagnostics. Current approaches require time-consuming bacterial isolation and enrichment procedures, delaying stratified treatment. Here, we describe a biomarker-based strategy that utilises bacterial small molecular metabolites and lipids for direct detection of bacteria in complex samples using mass spectrometry (MS). A spectral metabolic library of 233 bacterial species is mined for markers showing specificity at different phylogenetic levels. Using a univariate statistical analysis method, we determine 359 so-called taxon-specific markers (TSMs). We apply these TSMs to the in situ detection of bacteria using healthy and cancerous gastrointestinal tissues as well as faecal samples. To demonstrate the MS method-agnostic nature, samples are analysed using spatial metabolomics and traditional bulk-based metabolomics approaches. In this work, TSMs are found in >90% of samples, suggesting the general applicability of this workflow to detect bacterial presence with standard MS-based analytical methods., Competing Interests: Competing interests: The authors declare no competing interest related to this work., (© 2024. The Author(s).) more...

The worrisome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram-negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products from the bacterium Xanthomonas albilineans . Albicidin, which effectively targets the bacterial DNA-gyrase, is a lipophilic hexapeptide mostly consisting of para amino benzoic acid units and only one α-amino acid. In this study, we report on the design and synthesis of new albicidins, containing N-atoms on each of the 5 different phenyl rings. We systematically introduced N-atoms into the aromatic backbone to monitor intramolecular H-bonds and for one derivative correlated them with a significant enhancement of the antibacterial activity and activity spectrum, particularly also towards Gram-positive bacteria. In parallel we conducted DFT calculations to find the most stable conformation of each derivative. A drastic angle-change was observed for the lead compound and shows a preferred planarity through H-bonding with the introduced N-atom at the D-fragment of albicidin. Finally, we went to the next level and conducted the first in vivo experiments with an albicidin analogue. Our lead compound was evaluated in two different mouse experiments: In the first we show a promising PK profile and the absence of toxicity and in the second very good efficiency and reduction of the bacterial titre in an E. coli infection model with FQ-resistant clinically relevant strains. These results qualify albicidins as active antibacterial substances with the potential to be developed as a drug for treatment of infections caused by Gram-negative and Gram-positive bacteria., Competing Interests: FOG is employee of Gombert Pharma Research Solutions (GPRS) and shareholder of Selmod LLC. The other authors declare no conflict of interest. Patents are filed., (This journal is © The Royal Society of Chemistry.) more...

Albicidin is a potent antibacterial oligoaromatic peptide that is susceptible to the protease AlbD, a resistance factor. This potentially restricts the use of albicidin as a drug. To overcome this obstacle, we synthesized and evaluated six analogues with isosteric replacement of the key amide link. Protease stability was established while maintaining the antibacterial activity, including three analogues with up to eight times higher activity compared with the natural albicidin. more...

The E and Z geometric isomers of a stable silene (tBu 2 MeSi)(tBuMe 2 Si)Si=CH(1-Ad) (1) were synthesized and characterized spectroscopically. The thermal Z to E isomerization of 1 was studied both experimentally and computationally using DFT methods. The measured activation parameters for the 1Z⇌1E isomerization are: E a =24.4 kcal mol -1 , ΔH ≠ =23.7 kcal mol -1 , ΔS ≠ =-13.2 e.u. Based on comparison of the experimental and DFT calculated (at BP86-D3BJ/def2-TZVP(-f)//BP86-D3BJ/def2-TZVP(-f)) activation parameters, the Z⇌E isomerization of 1 proceeds through an unusual (unprecedented for alkenes) migration-rotation-migration mechanism (via a silylene intermediate), rather than through the classic rotation mechanism common for alkenes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

The understanding of structure-function relationships within synthetic biomimetic systems is a fundamental challenge in chemistry. Herein we report the direct correlation between the structure of short peptoid ligands-N-substituted glycine oligomers incorporating 2,2'-bipyridine groups-varied in their monomer sequence, and the photoluminescence of Ru II centers coordinated by these ligands. Based on circular dichroism and fluorescence spectroscopy we demonstrate that while helical peptoids do not affect the fluorescence of the embedded Ru II chromophore, unstructured peptoids lead to its significant decay. Transmittance electron microscopy (TEM) revealed significant differences in the arrangements of metal-bound helical versus unstructured peptoids, suggesting that only the latter can have through-space interactions with the ruthenium dye leading to its quenching. High-resolution TEM enabled the remarkable direct imaging of singular ruthenium-bound peptoids and bundles, supporting our explanation for structure-depended quenching. Moreover, this correlation allowed us to fine-tune the luminescence properties of the complexes simply by modifying the sequence of their peptoid ligands. Finally, we also describe the chiral properties of these Ru-peptoids and demonstrate that remote chiral induction from the peptoids backbone to the ruthenium center is only possible when the peptoids are both chiral and helical., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

The first two persistent silenyl radicals (R 2 C=Si . -R), with a half-life (t 1/2 ) of about 30 min, were generated and characterized by electron paramagnetic resonance (EPR) spectroscopy. The large hyperfine coupling constants (hfccs) (a( 29 Si α )=137.5-148.0 G) indicate that the unpaired electron has substantial s character. DFT calculations, which are in good agreement with the experimentally observed hfccs, predict a strongly bent structure (∡C=Si-R=134.7-140.7°). In contrast, the analogous vinyl radical, R 2 C=C . -R (t 1/2 ≈3 h), exhibits a small hfcc (a( 13 C α )=26.6 G) and has a nearly linear geometry (∡C=C-R=168.7°)., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

Peptoids, N-substituted glycine oligomers, are an important class of foldamers that can adopt polyproline-type helices (PP-I and PP-II), given that the majority of their sequence consists of chiral, bulky side chains. Herein a new approach for the stabilization of a pure PP-I-like peptoid helix through metal coordination is introduced. A systematic spectroscopic study was performed on a series of peptoid heptamers bearing two 8-hydroxyquinoline ligands at fixed positions, and a mixture of chiral benzyl and alkyl substituents in varied positions along the peptoid backbone. When the benzyl groups are located at the 3rd and 4th positions, the peptoid (7P6) gives upon Cu 2+ binding a circular dichroism (CD) signal similar to that of a PP-I helix. Exciton couplet CD spectroscopy and EPR spectroscopy, as well as modifications to the length of 7P6 and derivatization through acetylation provided insights into the unique folding of 7P6 upon Cu binding, showing that it is led by two competing driving forces, namely coordination geometry and sequence., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...

The first two lithium silenides, Li(tBu(2)MeSi)Si═C(SiMetBu(2))(1-Ad) (1) and Li(tBuMe(2)Si)Si═C(SiMetBu(2))(1-Ad) (2) were prepared by THF addition to the corresponding lithium-silenolates, [(tBu(2)MeSi)(2)Si═C(OLi)(1-Ad)]·(R(3)SiLi) (3a: R(3)Si═tBu(2)MeSi, 3b: R(3)Si═tBuMe(2)Si). 1 and 2 were crystallized, and their structures were determined by X-ray crystallography. This process requires the presence of both coaggregated silyllithium (R(3)SiLi) (3a and 3b) and THF. Based on reaction products and DFT calculations, it is suggested that elimination of tBu(2)MeSiOLi from 3a (or 3b) produces first the corresponding silyne intermediate which rearranges to the corresponding silylidene, which is then trapped by R(3)SiLi giving 1 (or 2). more...