Carbon monoxide-releasing molecules as therapeutic agents to promote wound healing
Final Report Abstract
Carbon monoxide is now well-recognized as an important small signalling mediator in the human body. In addition to its endgenous enzymatic production from heme by heme oxygenase (HO), there is also considerable biomedical interest in metal carbonyl complexes and other carrier compounds as CO-releasing molecules (CORMs). Inspired by the finely tuned balance between cytoprotective and cytotoxic activity, CORMs are now studied for a range of therapeutic applications. Based on the recognition of the role of HO in wound healing and the ease of topical application of CORM prodrugs in combination with photoactivation, the aim of this project was to explore novel CO releasing molecules conjugated to cellular targeting vectors, contrast these molecular systems with CO-loaded nanomaterials, and study their biological activity in the promotion of wound healing. Based on a generalized synthetic approach, both the "CO-release sphere" and the "drug sphere" of manganese tricarbonyl-based CORMs were widely modified and the CO carrier moiety attached to a range of targeting vectors aimed at cellular membranes, nuclear DNA, and the mitocondria. In addition, Re congeners of the Mn title compounds were also prepared and showed promising properties for intracellular tracking using fluorescence microscopy. Immobilization of metal carbonyl complexes in the inner pores of metal-organic frameworks (MOFs) lead to significantly higher loading than surface functionalization demonstrated in previous works, but the characterization and further optimization of these CORM nanomaterials was hampered by relocation of a key collaborator. Still, promising biological activity was demonstrated for selected new CORMs, including significant antibacterial potency on clinical isolates of pathogenic bacterial strains, which are also relevant in the context of wound infections. One of the title compounds turned out to be non-toxic even at very high concentration and showed significant bacterial clearance in two in vivo model systems. In particular, in initial animal experiments with chicken infected with Avian pathogenic E. coli, a significant reduction in bacterial load by at least one order of magnitude was observed after single dose oral treatment with the lead compound at 20 mg/kg, demonstrating the promise of metal complexes in biomedical applications. In particular, the non-toxicity of the manganese carbonyl compounds at 80 mg/kg (equivalent to 6 g for a 75 kg human) defies the general opinion that metal complexes are generally toxic and therefore unsuitable for drug development. In summary, in this project, the scope of CO-releasing molecules (CORMs) has been significantly expanded to feature a wide range of biological carrier systems, which will help to elucidate the primary cellular structures relevant for CO bioactivity. The challenge is now to orchestrate the various further biological assays under way and further advance the main lead compound to applications e.g. in animal health.
Publications
- „Antimicrobial activity of the manganese photo-activated CO-releasing molecule [Mn(CO)3(tpa-k3N)]+ against a multidrug-resistant Eschericha coli”, Antioxid. Redox Signal. 2016, 24, 765–780
M. Tinajero-Trejo, N. Rana, T.W. Smith, C. Nagel, M.F. Hippler, U. Schatzschneider, R.K. Poole
(See online at https://doi.org/10.1089/ars.2015.6484) - „Small signaling molecules and CO-releasing molecules (CORMs) for the modulation of the cellular redox metabolism” in: I. Batinic-Haberle, J.S. Reboucas, I. Spasojevic (eds.) Redox-active therapeutics, Springer, Cham, 2016
P.V. Simpson, U. Schatzschneider
(See online at https://doi.org/10.1007/978-3-319-30705-3_13) - „A manganese photosensitive tricarbonyl molecules [Mn(CO)3(tpa-k3N)]Br enhances antibiotic efficacy in a multi-drug-resistent Escherichia coli", Microbiology 2017, 163, 1477–1489
N. Rana, H. Jesse, M. Tinajero-Trejo, J. Butler, M.L. von und zur Mühlen, C. Nagel, U. Schatzschneider, R.K. Poole
(See online at https://doi.org/10.1099/mic.0.000526) - „Antimicrobial activity of carbon monoxide-releasing molecule [Mn(CO)3(tpa-3N)]Br versus multidrug-resistant isolates of Avian Pathogenic Escherichia coli and its synergy with colistin”, PLOS ONE 2017, 12, e0186359
J. Betts, C. Nagel, U. Schatzschneider, R. Poole, R.M. la Ragione
(See online at https://doi.org/10.1371/journal.pone.0186359) - „Metal complexes as delivery systems for CO, NO, and H2S to explore the signaling network of small-molecule messengers” in: K.K.-W. Lo (ed.) Interactions of inorganic and organometallic transition metal complexes with biological molecules and living cells, Academic Press, Cambridge, 2017
U. Schatzschneider
(See online at https://doi.org/10.1016/B978-0-12-803814-7.00006-X) - „Antimicrobial activity of organometal compounds: Past, present, and future prospects” in: T. Hirao, T. Moriuchi (eds.) Advances in Bioorganometallic Chemistry, Elsevier, Amsterdam, 2018
U. Schatzschneider
(See online at https://doi.org/10.1016/B978-0-12-814197-7.00009-1) - „Biological activity of manganese(I) tricarbonyl complexes on multidrugresistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella”, Metallomics 2019, 11, 2033–2042
P. Güntzel, C. Nagel, J. Weigelt, J.W. Betts, C.A. Pattrick, H.M. Southam, R.M. La Ragione, R.K. Poole, U. Schatzschneider
(See online at https://doi.org/10.1039/c9mt00224c) - „Wavelength-dependent control of the CO release kinetics of manganese(I) tricarbonyl PhotoCORMs with benzimidazole coligands”, Eur. J. Inorg. Chem. 2019, 4572–4581
A. Mansour, C. Steiger, C. Nagel, U. Schatzschneider
(See online at https://doi.org/10.1002/ejic.201900894)
