“We are at risk of entering an era where currently available antibiotics are no longer effective against bacteria that have developed resistance against them. In the past 10 years, very few new antibiotics have entered the market. Part of the reason for this is that only a handful of large pharmaceutical companies continue to be involved in their development. In addition, Gram-negative bacteria have started to develop resistance against even the latest antibiotics used to treat related infections,” says Paula Kiuru, docent of medicinal chemistry at the Faculty of Pharmacy, University of Helsinki.
Developing pharmaceutical agents against Gram-negative bacteria is a particular challenge, since the dual structure of their cell wall effectively prevents many compounds from entering the bacterial cell. In Gram-positive bacteria, the cell wall is single-layered.
“However, we were able to advance antibiotic compounds that are effective against Gram-negative bacteria into the first clinical trials conducted among healthy study subjects under the international and extensive ENABLE project,” Kiuru says.
In the latest study, an international group of researchers further developed and optimised compounds discovered by Schofield group at the University of Oxford that imitate in their binding function penicillins, cephalosporins, carbapenems and other antibiotics in the β-lactam group.
“Metallo-β-lactamase (MBL) enzymes in bacterial strains resistant to β-lactam antibiotics are capable of breaking down the β-lactam structure of, for example, carbapenem. In contrast, the same enzymes are unable to break down the new type of indole-2-carboxylate structure we have developed. A combination of the new compounds and carbapenem antibiotics is also more effective against resistant bacteria, as the new compound bound to the MBL enzyme prevents it from breaking down the antibiotic,” Kiuru notes.
The goal is to advance to clinical trials in the near future the novel indole-2-carboxylate derivative developed in the study, which imitates the binding of β-lactams with MBL enzymes.
“The goal of this research is to develop a new antibiotic drug especially for developing countries where bacterial strains resistant to carbapenems are abundant. The seven-year ENABLE project has been able to bring together more research groups than usual from different fields as well as sufficient resources to carry out early-stage drug development and trials as a well-functioning whole. The project is an excellent example of effective and productive collaboration between the pharmaceutical industry and various academic operators. In Finland too, more long-term funding and coordination is needed in research on antibiotics, since drug development projects need more than a few years to advance far enough,” Kiuru says.
The ENABLE project funded by the European Innovative Medicines Initiative (IMI) partnership was coordinated by Uppsala University under the direction of Professor Anders Karlén, and GlaxoSmithKline. Developers of promising new antibiotic candidates, academic groups and pharmaceutical companies were able to apply to join the ENABLE project and benefit from the resources of its antibiotic research environment. From among 110 applicants, a total of 23 antibiotic candidates were admitted. From the Faculty of Pharmacy, contributing to the project were Professor Jari Yli-Kauhaluoma and Docent of Medicinal Chemistry Paula Kiuru as well as Postdoctoral Researchers Andrew Neal, Raisa Haavikko and Piyushkumar Patel.
Articles:
Brem, J., Panduwawala, T., Hansen, J. U., Hewitt, J., Liepins, E., Donets, P., Espina, L., Farley, A., Shubin, K., Gomez Campillos, G., Kiuru, P., Shishodia, S., Krahn, D., Lesniak, R., Schmidt, A., J., Calvopina, K., Turrientes, M. C., Kavanagh, M., Lubriks, D., Hinchliffe, P., Langley, G., Aboklaish, A., Eneroth, A., Backlund, M., Baran, A. G., Nielsen, E., Speake, M., Kuka, J., Robinson, J., Grinberga, S., Robinson, L., McDonough, M., Rydzik, A., Leissing, T., Jimenez-Castellanos, J. C., Avison, M. B., de Silva Pinto, S., Panifer, A., Martjuga, M., Widlake, E., Priede, M., Hopkins Navratilova, I., Gniadkowski, M., Belfrage, A. K., Yli-Kauhaluoma, J., Bacque, E., Page, M. G. P., Björkling, F., Tyrrell, J., Spencer, J., Baranczewski, P., Canton, R., McElroy, S. P., Jones, P., Baquero, F., Suna, E., Morrison, A., Walsh, T. R., and Schofield, C. J. Imitation of β -Lactam Binding Enables Broad Spectrum Metallo-β-Lactamase Inhibitors. Nature Chem. 2022, 14, 15-24., https://doi.org/10.1038/s41557-021-00831-x
Olliver, M., Griestop, L., Hughes, D., Belfrage, A. K., Gising, J., Baranczewski, P., Vingsbo Lundberg, C., Karlén, A. ENABLE: an engine for European antibacterial drug discovery and development. Nature Rev. Drug Discov. 2021, 20, 407-8. https://doi.org/10.1038/d41573-021-00074-y