Scientists discover new class of antibiotics effective against drug-resistant bacteria

Scientists at Uppsala University have identified a new class of antibiotics that is effective against resistant bacteria and shows promise in mouse models. This discovery, targeting a novel bacterial protein, could lead to essential treatments for infections previously considered untreatable, marking a crucial advance in the ongoing battle against antibiotic resistance.

Researchers at Uppsala University have discovered a new class of antibiotics with potent activity against multidrug-resistant bacteria, and shown that it cures bloodstream infections in mice. The new class of antibiotics is described in a study recently published in the journal PNAS.

Antibiotics are the foundation of modern medicine and have dramatically improved the lives of people around the world over the past century. Today we tend to take antibiotics for granted and rely heavily on them to treat or prevent bacterial infections, for example to reduce the risk of infections during cancer therapy, during invasive surgery and transplants, and in mothers and premature babies.

However, the global increase in antibiotic resistance increasingly threatens their effectiveness. To guarantee access to effective antibiotics in the future, the development of new therapies to which there is no existing resistance is essential.

New innovative research

Researchers from Uppsala University recently published their work in the Proceedings of the National Academy of Sciences of the USA, describing a new class of antibiotics developed as part of multinational consortia. The class of compounds they describe targets a protein, LpxH, used by Gram-negative bacteria in a pathway to synthesize their outer layer of protection against the environment, called lipopolysaccharide.

Not all bacteria produce this layer, but those that do include the organisms identified by the World Health Organization as the most critical to develop new treatments for, including Escherichia coli And Klebsiella pneumoniae who have already developed resistance to available antibiotics. The researchers were able to demonstrate that this new class of antibiotics is highly active against multidrug-resistant bacteria and could treat bloodstream infections in a mouse model, demonstrating the promise of this class.

Importantly, since this class of compounds is completely new and the protein LpxH has not yet been exploited as a target for antibiotics, there is no pre-existing resistance to this class of compounds. This contrasts with the many “me-too” antibiotics from existing classes currently in clinical development. Although the current results are promising, significant additional work will be required before compounds of this class are ready for clinical trials.

Reference: “Antibiotic class with potent in vivo activity targeting the synthesis of lipopolysaccharides in Gram-negative bacteria” by Douglas L. Huseby, Sha Cao, Edouard Zamaratski, Sanjeewani Sooriyaarachchi, Shabbir Ahmad, Terese Bergfors, Laura Krasnova, Juris Pelss, Martins Ikaunieks , Einars Loza, Martins Katkevics, Olga Bobileva, Helena Cirule, Baiba Gukalova, Solveiga Grinberga, Maria Backlund, Ivailo Simoff, Anna T. Leber, Talía Berruga-Fernández, Dmitry Antonov, Vivekananda R. Konda, Stefan Lindström, Gustav Olanders, Peter Brandt, Pawel Baranczewski, Carina Vingsbo Lundberg, Edgars Liepinsh, Edgars Suna, T. Alwyn Jones, Sherry L. Mowbray, Diarmaid Hughes and Anders Karlén, April 5, 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2317274121

The work to discover and develop this new class of antibiotics was supported by the EU project ENABLE, which was funded through the New Drugs 4 Bad Bugs (ND4BB) program of the Innovative Medicines Initiative. The ENABLE project, led by researchers from Uppsala University and the pharmaceutical company GlaxoSmithKline, brought together stakeholders from across Europe, representing academia and large and small pharmaceutical companies, to pool resources and expertise to advance the early development of antibiotics to improve. This class of antibiotics is now being further developed in the follow-on project ENABLE-2, an antibiotic drug discovery platform funded by the Swedish Research Council, the National Antibiotic Resistance Research Program and the Swedish innovation agency Vinnova to continue the momentum generated by the original ENABLE- project.