Spexis announces the publication of promising results for a novel class of macrocyclic, peptidomimetic antibiotics in Science Advances
Spexis AG / Key word(s): Scientific publication
Allschwil, Switzerland, June 6, 2023
Spexis announces the publication of promising results for a novel class of macrocyclic, peptidomimetic antibiotics in Science Advances demonstrating potent in vitro and in vivo antimicrobial activity against MDR and XDR Enterobacteriaceae, including carbapenem-resistant and colistin-resistant strains
Spexis AG (SIX: SPEX), a clinical-stage biopharmaceutical company focused on rare diseases and oncology, today announced the publication of preclinical results from the company’s novel class of macrocyclic, peptidomimetic antibiotics developed in collaboration with the University of Zurich, demonstrating potent in vitro and in vivo antimicrobial activity against multidrug resistant (MDR) and extensively drug resistant (XDR) Enterobacteriaceae. The manuscript, titled “Peptidomimetic Antibiotics Disrupt the Lipopolysaccharide Transport Bridge of Drug-Resistant Enterobacteriaceae,” is available online in the international peer-reviewed journal Science Advances at: https://www.science.org/doi/10.1126/sciadv.adg3683.
Antimicrobial resistance (AMR) has emerged as a significant threat for both patients and healthcare systems. According to the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), bacterial AMR is associated with the deaths of approximately 5 million people worldwide each year. In the United States, more than 2.8 million antimicrobial-resistant infections occur each year, leading to over 35,000 deaths and an estimated USD 4.6 billion in healthcare costs. On a global scale, the WHO estimates the overall economic burden from the emergence of AMR, including impact on international trade and healthcare expenses, could cost the world economy USD 100 trillion by 2050.
MDR, XDR, and carbapenem-resistant and colistin-resistant Enterobacteriaceae, specifically Klebsiella pneumoniae and Escherichia coli, have been identified by the WHO as priority one Gram-negative pathogens in the fight against AMR. Carbapenem-resistant Klebsiella pneumoniae strains exhibiting hypervirulence and resistance have been associated with overall mortality up to 84% according to the European Centre for Disease Prevention and Control (ECDC). The ECDC also projects that resistant Enterobacteriaceae have a high potential to cause outbreaks in healthcare and community settings with global dissemination a major concern. As antibiotic use increases, selective pressures on microbes increase, frequently leading to the development of resistance. Recent discovery of plasmid-mediated transferable colistin resistance genes have shown the ease with which resistance can spread in bacterial populations. These transferable genes are often transmitted with other resistance genes, leading to strains of multi-drug resistant bacteria. Data from a multinational prospective cohort study published in The Lancet showed that carbapenem resistance was associated with an increased length of hospital stays and increased probability of in-hospital mortality. Even countries with judicious antibiotic use have seen the prevalence of resistance doubling in the past 5 years according to a study in the British Medical Journal.
In close collaboration with Professor Oliver Zerbe’s lab at the University of Zurich and with financial and scientific support from Innosuisse and CARB-X, Spexis utilized its proprietary macrocycle platform to identify a novel class of antibiotics to potentially address these emerging threats.
“We are very proud of our team to have discovered, with our partners, a novel class of macrocyclic, peptidomimetic antibiotics targeting an essential pathway in the lipopolysaccharide transport by applying our unique peptidomimetic macrocycle-based discovery platform,” said Jeff Wager, M.D., Chairman & CEO of Spexis. “The described antibiotics have the potential to become a valuable addition and alternative to the current arsenal of standard of care antibiotics in the fight against difficult-to-treat infections. This is yet another example of the power of both our macrocycle platforms, PEMFinder® and MacroFinder®, to drug highly relevant targets with novel therapeutic candidates.’’
The published manuscript in Science Advances highlights the lead compounds from this novel peptidomimetic antibiotics class demonstrating favorable drug-like properties with excellent minimum inhibitory concentrations (MICs) against a broad panel of MDR, XDR, and carbapenem-resistant and colistin-resistant Enterobacteriaceae. The compounds showed potent in vivo efficacy, especially in lung infection models as well as a promising in vitro and in vivo safety profile. Mechanism of action studies showed the lead compounds disrupt the essential lipopolysaccharide transport bridge (Lpt) by binding with low nanomolar affinity to the lipopolysaccharide transport protein A (LptA), a novel antibiotic target, and are able to overcome the key Q62L mutation in LptA. No cross-resistance with standard of care antibiotics was observed and the demonstrated Enterobacteriaceae-specificity versus broad-spectrum activity supports continued development for this class of antibiotics for the potential management and treatment of antimicrobial resistant pathogens.
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Spexis (SIX: SPEX) is a clinical-stage biopharmaceutical company based in Allschwil, Switzerland, focused on rare diseases and oncology. For further information please visit: www.spexisbio.com.
This press release contains forward-looking statements which are based on current assumptions and forecasts of Spexis management. Known and unknown risks, uncertainties, and other factors could lead to material differences between the forward-looking statements made here and the actual development, in particular Spexis’ results, financial situation, and performance. Readers are cautioned not to put undue reliance on forward-looking statements, which speak only of the date of this communication. Spexis disclaims any intention or obligation to update and revise any forward-looking statements, whether as a result of new information, future events or otherwise.
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