New papers in RSC Medicinal Chemistry and ACS Omega: Two new routes into antibiotic chemical space
Work from the Bacterial Defense Systems and Antimicrobial Resistance Group, led by James Booth and Emily Helgesen at the Department of Microbiology, together with Henrik Franzyk's laboratory at the University of Copenhagen, has produced two new papers on antibiotic candidates built outside the compound classes now in clinical use. One paper, in RSC Medicinal Chemistry, builds peptidomimetics from short peptide fragments attached to small-molecule scaffolds. The other, in ACS Omega, derives antimicrobial peptides from TisB, a toxin bacteria produce as part of their own physiology. Both papers aim at chemical space that existing resistance mechanisms have not already been selected against.
Summary from the authors:
Why look beyond natural products
Most antibiotics in clinical use, and most candidates still in development, belong to existing compound classes built on natural products. Resistance already circulating against those classes tends to carry over quickly to new members of the same class. Our two new papers take a different route into new chemical space.
A bigger design space
For RSC Medicinal Chemistry, we synthesized peptidomimetics by attaching short peptide fragments to small-molecule scaffolds, instead of screening natural extracts. A handful of fragments combined with a handful of scaffolds already produces a wide structural range, a small fraction of what is combinatorially possible. Several compounds reached minimum inhibitory concentrations (MICs) of 8 μg/mL or below against at least one of the Gram-negative and Gram-positive species tested. Against an ESBL-producing E. coli strain, most of these compounds retained MICs very similar to those against the wild-type strain, though activity dropped against a separately tested carbapenem-resistant E. coli isolate. At twice the MIC, several compounds were bactericidal in E. coli within 24 hours, and hemolysis and fibroblast-viability assays showed an acceptable safety margin for a subset of compounds, at concentrations 50- to 100-fold above their MICs.
A different source entirely
In ACS Omega, we went straight to a toxin bacteria make themselves. Type I toxin-antitoxin systems encode small membrane-active peptides as part of normal bacterial physiology. TisB is one of them: tightly repressed under native conditions, highly toxic once derepressed, and lethal to bacteria by collapsing the membrane's proton motive force. Rather than bioprospecting an unknown compound and spending years on target deconvolution, we started from a toxin whose bactericidal mechanism was already understood.
We designed 44 peptides derived from TisB across three rounds of optimization. The best of them reached MICs of 2 to 16 μM against Gram-negative bacteria (E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii) with an acceptable hemolysis profile; Gram-positive bacteria were less susceptible. In E. coli, four of the least hemolytic peptides lowered azithromycin's MIC 8- to 16-fold, bringing it 16-fold below its clinical breakpoint. In K. pneumoniae, two peptides potentiated azithromycin at concentrations as low as 0.25 to 0.5 μM, low enough to suggest repurposing azithromycin against K. pneumoniae lung infections as a possibility worth exploring.
Not a fringe idea
Peptide-based antibiotics already have an established place in the clinic. Polymyxins, daptomycin, and bacitracin are all on the market.
Collaboration
Both papers were carried out with our collaborator Henrik Franzyk and his collaborators and his laboratory at the Department of Drug Design and Pharmacology, University of Copenhagen. Colleagues at the Department of Microbiology, Oslo University Hospital, and the Norwegian University of Science and Technology (NTNU) contributed to both papers. Primary funding came from the Research Council of Norway, with additional support from the Novo Nordisk Foundation, Helse Sør-Øst RHF, Felles Forskningsutvalg and NORM. Both papers' hemolysis assays cite the methodology we established in an earlier, highly cited paper on optimizing the hemolysis assay for cytotoxicity testing.
Together, the two papers point to peptide chemistry, built either from small-fragment libraries or from bacteria's own toxins, as a source of antibacterial leads outside the resistance landscape shaped by seventy years of natural-product-derived antibiotics.
Links:
Link to the papers:
Dyhr E, Cañete de Pinedo L, Frederiksen N, Bojer MS, Ingmer H, Sæbø IP, Ræder SB, Bjørås M, Helgesen E, Booth JA, Franzyk H (2026) Antibacterial peptidomimetics via fragment display on small-molecule scaffolds RSC Med. Chem., 17 DOI: 10.1039/D5MD00916B
Dyhr E, Sæbø IP, Riisnæs IMM, Bjørås M, Helgesen E, Booth JA, Franzyk H (2026) Antimicrobial Peptides Based on the TisB Toxin: Toward Enhanced Activity and Synergy with Antibiotics ACS Omega, 11 (26), 38837–38847 DOI: 10.1021/acsomega.6c02137
Related paper (methodology):
Sæbø IP, Bjørås M, Helgesen E, Booth JA, Franzyk H (2023) Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity Int J Mol Sci, 24 (3), 2914 DOI: 10.3390/ijms24032914
Link to research group:
OUH - Bacterial Defense Systems and Antimicrobial Resistance Group, headed by James Booth and Emily Helgesen