We search for antimicrobial agents to combat multidrug-resistant infections
Cancer and Infectious Diseases
Through interdisciplinary collaborations, the cluster aims at discovery and optimization of anticancer and/or antimicrobial lead compounds that combat emerging multidrug resistance. These are validated by in vitro and in vivo models. Our mission is to:
• Design peptides/peptidomimetics and small molecules that combat multidrug-resistant bacterial infections and identify novel targets
• Develop and apply cutting-edge technologies for identification of natural products with potential as antibiotics and chemotherapeutic leads
• Explore and validate novel anticancer compounds and targets
2023-02-01
A recent study led by Daniela De Zio highlights the complex role of Ambra1 in melanoma biology and immunotherapy response. We show that Ambra1 deficiency affects the tumor immune microenvironment by altering cytokine expression and reducing the infiltration of regulatory T cells (Treg) in an autophagy-dependent manner. We also demonstrate that the tumor become more sensitive to immunocheckpoint blockade-based therapy due to the absence of Ambra1, emphasizing Treg as a promising target for immunotherapy efficacy.
2023-01-18
This study published on Cell Reports shows that the loss of the S-nitrosoglutathione reductase (GSNOR), a crucial enzyme which controls the NO-mediated signaling inside the cell, promotes tumorigenesis by inducing the Focal Adhesion Kinase 1 (FAK1) oncogenic pathway. These findings point out GSNOR as a tumor suppressor gene.
2022-12-17
A study published in the journal Oncoimmunology, Daniela de Zio and coworkes show that pre-treatment of cancer with thiopurines increases the burden of mutations enhancing the anti-tumor immune response and the effect of immune checkpoint inhibitors. These findings pave the way for a phase I/II clinical trial that will explore whether treatment with thiopurines can increase the proportion of otherwise treatment-resistant cancer patients who may benefit from ICI therapy.
2022-12-16
In a recent study published in Journal of Bacteriology, Dan Staerk, Thomas Bjarnsholt and coworkers describe the mechanism and chemistry underlying Staphylococcus aureus' ability to inhibit Pseudomonas aeeruginosa growth in vitro.
2022-10-24
In a recent study published in Antibiotics, Hansen and coworkers describe the synthesis of C-locked analogues of the antimicrobial peptide BP214 which is an efficient strategy for obtaining cyclic lipopeptides.
2022-10-15
In a recent study led by Daniela De Zio and Elena Papaleo (Danish Cancer Society and DTU) published in Cell Death and Disease, a new bioinformatic tool Cancermuts, able to retrieve, annotate and prioritize cancer-associated mutations, was presented. Cancermuts can predict the pathogenic impact of missense cancer variants in any protein target. To validate the tool, AMBRA1 mutations in melanoma, where AMBRA1 is highly mutated and displays a tumor-suppressive role, were selected as a case study.
2022-09-26
In a collaborative study between L. Guardabassi (Prof., Dept. Veterinary and Animal Sciences, Univ. Copenhagen) and H. Franzyk it was found that E. coli (resistant to the first-line antibiotic neomycin) could be sensitized to macrolides relevant in veterinary medicine by combination with peptidomimetics. Interestingly, MICs of tilmicosin were reduced to levels achievable in the pig intestinal tract after oral administration, indicating a potential for its repurposing to manage E. coli enteritis in pigs.
Ma, Y.; Pirolo, M.; Subramani, P.; Gehring, R.; Damborg, P.; Franzyk, H.; Guardabassi, L. mSphere 2022, 7, https://doi.org/10.1128/msphere.00402-22
2022-02-11
In a recent study published in International Journal of Molecular Sciences, Hansen, Sheykhzhade and coworkers describe the synthesis of three different fluorescent analogues of α-calcitonin gene-related peptide with potent vasodilator activity. The analogues are promising tool compounds for further studies of the mechanism for internalization of CGRP receptors in live tissue and neuronal reuptake of the α-CGRP peptide.
2021-10-18
In a collaborative study led by Jan Stenvang and Dan Staerk, a natural product isolated from the Australian desert plant Eremophila galeata was shown to inhibit the Breast Cancer Resistance Pump (BCRP) involved in multidrug resistance. Docking studies show that the isolated compound binds to the same BCRP site as the active metabolite of the natural product-derived irinotecan, and this discovery opens up for design of new drug leads for reversal of BCRP-mediated multidrug resistance.
Drug Transporter Research Group:
https://drug.ku.dk/disciplines/peptides-and-proteins/drug-transporters/
Peptide-based Drug Research Group:
https://drug.ku.dk/disciplines/peptides-and-proteins/peptide-based-drug-research/
Natural Products Research Group:
https://drug.ku.dk/disciplines/peptides-and-proteins/natural-products-research-group/
Molecular Disease Biology:
https://drug.ku.dk/disciplines/molecular-and-cellular-pharmacology/molecular-disease-biology/
Melanoma Research Team:
https://www.cancer.dk/research/dcrc-research/cell-stress-and-survival/melanoma-research-team/
Frias, A.; Di Leo, L.; Antoranz, A.; Nazerai, L.; Carretta, M.; Bodemeyer, V.; Pagliuca, C.; Dahl, C.; Claps, G.; Mandelli, G.E.; Andhari, M.D.; Pacheco, M.P.; Sauter, T.; Robert, C.; Guldberg, P.; Madsen, D.H.; Cecconi, F.; Bosisio, F.M.; De Zio, D. Ambra1 modulates the tumor immune microenvironment and response to PD-1 blockade in melanoma. J. Immunother. Cancer. 2023 11, e006389. https://doi.org/10.1136/jitc-2022-006389
Rizza, S.; Di Leo, L.; Pecorari, C.; Giglio, P.; Faienza, F.; Montagna, C.; Maiani, E.; Puglia, M.; Bosisio, F.M.; Petersen, T.S.; Lin, L.; Rissler, V.; Viloria, J.S.; Luo, Y.; Papaleo, E.; De Zio, D.; Blagoev, B.; Filomeni, G. GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation. Cell Rep. 2023,42, 111997. https://doi.org/10.1016/j.celrep.2023.111997
Sæbø, I. P.; Bjørås, M.; Franzyk, H.; Helgesen, E.; Booth, J. A. Optimisation of the hemolysis assay for the assessment of cytotoxicity. Int. J. Mol. Sci. 2023, 24, 2914 (20 pages). https://doi.org/10.3390/ijms24032914
Plotniece, A.; Soboleva, A.; Supuran, C. T.; Carta, F.; Björkling, F.; Franzyk, H.; Yli-Kauhaluoma, J.; Augustyns, K.; Cos, P.; De Vooght, L.; Govaerts, M.; Aizawa, J.; Tammela, P.; Žalubovskis, R. Selected strategies to fight pathogenic bacteria. J. Enz. Inhib. Med. Chem. 2023, 38, 21554816 (27 pages). https://doi.org/10.1080/14756366.2022.2155816
Kyllesbech, C.; Trier, N. H.; Mughal, F. P.; Hansen, P. R.; Holmström, M. O.; El Fassi, D.; Hasselbalch, H.; Skov, V.; Kjær, L.; Ciplys, E.; Slibinskas, R.; Frederiksen, J. L.; Højrup,P.; Houen, G. Antibodies to calnexin and mutated calreticulin are common in human sera. Curr. Res. Transl. Med. 2023, 71, 103380 (13 pages). https://doi.org/10.1016/j.retram.2023.103380.
Hellewell, L.; Gilani, N. M.; Stanton, C.; Pelligand, L.; Franzyk, H.; Guardabassi, L.; Good, L. Efficacy of natural antimicrobial peptides versus peptidomimetic analogues: A systematic review. Future Med. Chem. 2022, 38, 2155816 (27 pages). https://doi.org/10.1080/14756366.2022.2155816
Ma, Y.; Pirolo, M.; Subramani, P.; Gehring, R.; Damborg, P.; Franzyk, H.; Guardabassi, L. Macrolide resistance and in vitro potentiation by peptidomimetics in porcine clinical Escherichia coli. mSphere 2022, 7, e00402-22 (10 pages). https://doi.org/10.1128/msphere.00402-22
Andersen, I. K. L.; Thomsen, T. T.; Rashid, J.; Bobak, T. R.; Oddo, A.; Franzyk, H.; Løbner-Olesen, A.; Hansen, P. R. C-locked analogs of the antimicrobial peptide BP214. Antibiotics 2022, 11, 1080 (10 pages). https://doi.org/10.3390/antibiotics11081080
Lone, A.; Nielsen, J.E.; Thulstrup, P.W.; Lund, R.; Hansen, P.R.; Jenssen, H. Cyclic N-locked indolicidin analogues with antimicrobial activity: Effect of ring size and fatty acid acylation. Eur. J. Med. Chem. Rep. 2022, 6, 100080 (7 pages). https://doi.org/10.1016/j.ejmcr.2022.100080
Viklund, M.; Fredriksson, J.; Holdfeldt, A.; Lind, S.; Franzyk, H.; Sundqvist, M.; Dahlgren, C.; Forsman, H. Structural determinants in the Staphylococcus aureus derived phenol-soluble modulin α2 peptide required for neutrophil formyl peptide receptor activation. J. Immunol. 2022, 208, 1632-1641. https://doi.org/10.4049/jimmunol.2101039
Petersen. M. J.; Xamuel L. Lund. X. L.; Semple, S. J.; Bevan Buirchell, B.; Franzyk, H.; Gajhede, H.; Kongstad, K. T.; Stenvang, J.; Staerk, D. Reversal of ABCG2/BCRP-mediated multidrug resistance by 5,3',5'-trihydroxy-3,6,7,4'-tetramethoxyflavone isolated from the Australian desert plant Eremophila galeata Chinnock. Biomolecules 2021, 11, 1534 (19 pages). https://doi.org/10.3390/biom11101534
Frederiksen, N.; Loukas, S.; Mudaliar, C.; Domraceva, I.; Kreichberga, A.; Pugovics, O.; Zabicka, D.; Tomczak, M.; Wygoda, W.; Björkling, F.; Franzyk, H. Peptide/β-peptoid hybrids with ultrashort PEG-like moieties: Effects on hydrophobicity, antibacterial and hemolytic properties. Int. J. Mol. Sci. 2021, 22, 7041 (17 pages). https://doi.org/10.3390/ijms22137041
Mood, E. H.; Goltermann, L.; Brolin, C.; Cavaco, L. M.; Yavari, N.; Frederiksen, N.; Nejad, A. J.; Franzyk, H.; Nielsen, P. E. Antibiotic potentiation in multidrug-resistant Gram-negative pathogenic bacteria by a synthetic peptidomimetic. ACS Infect. Dis. 2021, 7, 2152-2163. https://doi.org/10.1021/acsinfecdis.1c00147
Vestergaard, M.; Skive, B.; Domraceva, I.; Ingmer, H.; Franzyk, H. Peptide/β-peptoid hybrids with activity against vancomycin-resistant enterococci: Influence of hydrophobicity and structural features on antibacterial and hemolytic properties. Int. J. Mol. Sci. 2021, 22, 5617 (14 pages). https://doi.org/10.3390/ijms22115617
Loffredo, M.R.; Savini, F.; Bobone, S.; Casciaro, B.; Franzyk, H.; Mangoni, M. L.; Stella, L. Inoculum effect of antimicrobial peptides. Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2014364118 (10 pages). https://doi.org/10.1073/pnas.2014364118
Franzyk, H.; Christensen, S. B. Targeting toxins toward tumors. Molecules 2021, 26, 1292 (23 pages). https://doi.org/10.3390/molecules26051292
Frederiksen, N; Hansen, P. R.; Zabicka, D.; Tomczak, M.; Urbas, M.; Domraceva, I.; Björkling, F.; Franzyk, H. Peptide/peptoid hybrid oligomers: The influence of hydrophobicity on antibacterial activity and cell selectivity. ChemMedChem 2020, 15, 2544-2561. https://doi.org/10.1002/cmdc.202000526
Bing, C.; Wu, B. C.; Skovbakke, S. L.; Hancock, R. E. W.; Franzyk, H. In vivo anti-inflammatory activity of lipidated peptidomimetics Pam-(Lys-βNspe)6-NH2 and Lau-(Lys-βNspe)6-NH2 against PMA-induced acute inflammation. Front. Immunol. 2020, 11, 2102 (11 pages). https://doi.org/10.3389/fimmu.2020.02102
Jensen, S. K.; Thomsen, T. T.; Oddo, A.; Franzyk, H.; Anders Løbner-Olesen, A.; Hansen, P. R. Novel cyclic lipopeptide antibiotics: Effects of acyl chain length and position. Int. J. Mol. Sci. 2020, 21, 5829 (18 pages). https://doi.org/10.3390/ijms21165829
Frederiksen, N; Hansen, P. R.; Björkling, F.; Franzyk, H. Peptide/peptoid hybrid oligomers: Influence of hydrophobicity and relative side-chain length on antibacterial activity and cell selectivity. Molecules 2019, 24, 4429 (18 pages). https://doi.org/10.3390/molecules24244429
Baker, K. R Jana, B.; Hansen, A. M.; Vissing, K. J.; Nielsen, H. M.; Franzyk, H.; Guardabassi, L. Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptidomimetics. Front. Cell. Infect. Microbiol. 2019, 9, 236 (13 pages). https://doi.org/10.3389/fcimb.2019.00236
Christensen, M. V.; Kongstad, K. T.; Søndergaard, T. E.; Staerk, D.; Nielsen, H. M.; Franzyk, H.; Wimmer, R. 19F-substituted amino acids as an alternative to fluorophore labels: monitoring of degradation and cellular interactions of analogues of penetratin by 19F NMR. J. Biomol. NMR 2019, 73, 167-182. https://doi.org/10.1007/s10858-019-00239-3
Hansen, A. M.; Bonke, G.; Hogendorph, W. F. J.; Björkling, F.; Nielsen, J.; Nielsen, P. E.; Kongstad, K. T.; Zabicka, D.; Franzyk. H. Microwave-assisted solid-phase synthesis of antisense acpP peptide nucleic acid-peptide conjugates active against colistin- and tigecycline-resistant E. coli and K. pneumoniae. Eur. J. Med. Chem. 2019, 168, 134-145. https://doi.org/10.1016/j.ejmech.2019.02.024
Molchanova, N.; Wang, H.-Z.; Hansen, P.; Nielsen, H. M.; Høiby, N.; Franzyk, H. Antimicrobial activity of α-peptide/β-peptoid lysine-based peptidomimetics against colistin-resistant Pseudomonas aeruginosa isolates from cystic fibrosis patients. Front. Microbiol. 2019, 10, 275 (9 pages). https://doi.org/10.3389/fmicb.2019.00275
Baker, K. R.; Jana, B.; Hansen, A. M.; Vissing, K. J.; Nielsen, H. M.; Franzyk, H.; Guardabassi, L. Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptide potentiators. Int. J. Antimicrob. Agents 2019, 53, 868-872. https://doi.org/10.1016/j.ijantimicag.2018.10.025
Cluster Leader
Henrik Franzyk
Associate professor
henrik.franzyk@sund.ku.dk
Communications Representative
Dan Stærk
Professor
ds@sund.ku.dk
Core members
| Name | Title | Image |
|---|---|---|
| Henrik Franzyk | Associate Professor |
|
| Jan Stenvang | Associate Professor |
|
| Osman Asghar Mirza | Associate Professor |
|
| Paul Robert Hansen | Associate Professor |
|
| Tri Hien Viet Huynh | Associate Professor |
|