Deciphering the Mechanisms of Action of Salt-Insensitive King Penguin Defensins to enter the “Arms Race” against Pathogens – ANTARBioTic

The ANTARBioTic project is fitting with the objectives of Biomedical Innovation, in line with the “Antibiotic Resistance” program. Two sentences caught our attention in a recent report of the WHO on antimicrobial resistance, which are pushing ANTARBioTic ahead. The first one states: “overall, the clinical pipeline and recently approved antibiotics are insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance (AMR).” The second one is even more encouraging for us: “the newly approved agents have limited clinical benefit over existing treatment, as over 80% are from existing antibiotic classes”. In January 2022, a publication in The Lancet confirmed that AMR poses a major threat to human health worldwide, causing more deaths in 2019 than AIDS and malaria combined. Nature, through biodiversity and evolution, provides series of natural antimicrobial peptides (AMPs), which are a heritage of innate immune responses, and essential weapons in our arsenal of natural defenses. It is well recognized that one of the most promising avenues of research for alternatives to so-called conventional antibiotics, which are conducive to the rapid acquisition of resistance, is the identification, improvement and/or development of natural AMPs, which are believed to have a low probability of inducing resistance. ANTARBioTic is a bioinspired project whose priority objectives are (1) to enrich our knowledge on the molecular diversity of Spheniscins (Sphe, avian beta defensins), AMPs isolated from the stomach of the king penguin that control the microbiote in a highly saline environment, and (2) to decipher their mechanisms of action. To develop an antibiotic, the primary issue is to decipher its mode of action, which will be the major goal of ANTARBiotic, thanks to up-to-date in vivo biophysics methods (solid state NMR and fluorescent microscopy on living bacteria), as well as proteomics applied to study how Sphe alter selected micro-organisms (bacteria and filamentous fungi). Our project will also generate biological and structural data that will serve to evaluate the potential for valorization of Sphe as anti-infective agents. To achieve these objectives, ANTARBioTic relies on an "interactome", the four-leaf clover of ANTARBioTic, made up of four partners with complementary and internationally peer-recognized expertise in biodiversity, biochemistry, biophysics and structural biology.