Revealing the fundamental principles of picobodies with broad-spectrum and redox-responsive antibacterial activity

Antimicrobial resistance is a burning global issue.

The available antimicrobials are losing efficacy as resistant bacteria arise, but the industry does not invest enough into antibiotic discovery due to low expected revenues. Natural antimicrobial peptides (AMPs) hold great promise as blueprints for new antibiotics.

However, there are few known natural AMPs with sufficiently high potency and low toxicity that enable applications in veterinary and human medicine. As a result, the research on natural peptide antibiotics has been obstructed. New natural AMPs are needed urgently.

I propose for the first time that picobodies, recently discovered peptides part of natural cow antibodies, have potent antibacterial activity. In contrast to known mammalian AMPs, picobodies are exceptionally diverse due to the unique bovine immune system.

Moreover, all picobodies contain disulfide bonds that enable a redox regulation of their activity (unlike common antibiotics).

I suggest that redox-activated picobodies target bacteria in infection sites characterized by a reducing environment such as persistent bacterial biofilms.

In PicoBody, I have 4 major objectives: (i) interrogate natural picobody repertoires for antibacterial activity, (ii) investigate if cows can develop antibacterial picobodies against essential bacterial targets, (iii) understand how the redox environment regulates the antibacterial picobody activity, and (iv) evaluate the activity of antibacterial picobodies using in vitro and in vivo models.

To achieve my goals, I will employ a multidisciplinary approach based on protein science, molecular biology, microbiology, machine learning, and lab automation.

The project will establish key methods for the identification of antibacterial proteins, reveal basic insights about the fascinating bovine immune system, validate picobodies as previously unknown natural AMPs and open new research directions into the discovery of very much needed new peptide antibiotics.