Dataset Information

NATURAL PRODUCT DERIVED IANTHELLIFORMISAMINES INHIBIT PROTEIN TRANSLATION AND BLOCK BACTERIAL FLAGELLUM ASSEMBLY

ABSTRACT: Natural products have been a great source for novel drugs especially antibiotics. Given the current antibiotic crisis, revisiting poorly characterized antibacterial natural products may reveal novel modes of action (MoA) as inspiration for drug development. Here, we selected the natural product class of Ianthelliformisamines (Ian) as suitable candidates for MoA studies due to their reported activity against difficult to treat Gram-negative bacteria such as Escherichia coli. In addition, the electrophilic warhead facilitates covalent binding which enhances the residence time on targets and thereby could limit efflux mechanisms. Synthesis of three Ian analogs along with a chemical probe for activity-based protein profiling (ABPP) retained antibacterial effects which were enhanced in the presence of bicarbonate, an abundant ingredient of human serum. Chemical proteomics with the probe unraveled InfA, involved in the initiation of ribosomal protein biosynthesis, as an essential target which was confirmed by translation assays. Intriguingly, a virulence-associated target stood out as an additional hit, FliC, with a crucial role for flagellum assembly. The recombinant protein was probe-labeled and motility assays as well as transmission electron microscopy (TEM) imaging studies demonstrated impaired motility as well as flagellum assembly, respectively. Of note, this dual MoA translated into reduced invasion of pathogenic E. coli into human host cells highlighting a combined antibiotic/anti-virulence strategy as a promising and rather unexploited approach for further therapeutic development.

INSTRUMENT(S):

ORGANISM(S): Escherichia Coli

SUBMITTER: Max Bottlinger

LAB HEAD: Stephan A. Sieber

PROVIDER: PXD070366 | Pride | 2026-05-25

REPOSITORIES: Pride

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Natural Product-Derived Ianthelliformisamines Inhibit Protein Translation and Block Bacterial Flagellum Assembly.

Bottlinger Max M Morici Martino M Fajardo-Ruiz Elena E Gantner Isabella I Brameyer Sophie S Isselstein Michael M Berger Max M Wilson Daniel N DN Jung Kirsten K Sieber Stephan A SA

ACS chemical biology 20260421 5

Ianthelliformisamines (Ian) represent a poorly characterized natural product class reported to inhibit Gram-negative bacteria such as <i>Escherichia coli</i>. Given the current antibiotic crisis, revisiting poorly characterized antibacterial natural products may reveal novel modes of action (MoA) as inspiration for drug development. Thus, we elucidated the Ian mode of action and synthesized three Ian analogs along with a chemical probe for activity-based protein profiling (ABPP). All molecules r ...[more]

PMID: 42012457

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Project description:Background: Antibiotic resistance is an urgent threat to public health. Prior to the evolution of antibiotic resistance, bacteria frequently undergo response and tend to develop a state of adaption to the antibiotic. Ciprofloxacin is a broad-spectrum antibiotic by damaging DNA. With the widespread clinical application, the resistance of bacteria to ciprofloxacin continues to increase. This study aimed to investigate the transcriptome changes under the action of high concentration of ciprofloxacin in Escherichia coli. Results: We identified 773 up-regulated differentially expressed genes (DEGs) and 645 down-regulated DEGs in ciprofloxacin treated cells. Enriched biological pathways reflected the up-regulation of biological process such as DNA damage and repair system, toxin/antitoxin systems, formaldehyde detoxification system, peptide biosynthetic process and cellular protein metabolic process. With KEGG pathway analysis, up-regulated DEGs of kdsA and waa operon were associated with “LPS biosynthesis”. rfbABC operon was related to “streptomycin biosynthesis” and “polyketide sugar unit biosynthesis ”. Down-regulated DEGs of thrABC and fliL operons were associated with “flagellum-dependent cell motility” and “bacterial-type flagellum” in GO terms, and enriched into “biosynthesis of amino acids” and “flagellar assembly” in KEGG pathways. After treatment of ciprofloxacin, bacterial lipopolysacchride (LPS) release was increased by two times, and the mRNA expression level of LPS synthesis genes, waaB, waaP and waaG were elevated (P < 0.05). Conclusions: Characterization of the gene clusters by RNA-seq showed high dose of ciprofloxacin not only lead to damage of bacterial macromolecules and components, but also induce protective response against antibiotic action by up-regulating the SOS system, toxin/antitoxin system and formaldehyde detoxification system. Moreover, genes related to biosynthesis of LPS were also upregulated by the treatment indicating that ciprofloxacin can enhance the production of endotoxin on the level of transcription. These results demonstrated that transient exposure of high dose ciprofloxacin is double edged. Cautions should be taken when administering the high dose antibiotic treatment for infectious diseases.

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	20240222_6_1.mzML	Mzml
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	20240222_6_Ian-P-1_25_Ian-MPD-1_1.mzML	Mzml