Antimicrobial resistance is a pressing global challenge, as existing antimicrobials are losing their effectiveness due to the emergence of resistant bacteria. At the same time, the pharmaceutical industry has been reluctant to invest in new antibiotic discovery, primarily due to low expected revenues. Natural antimicrobial peptides (AMPs) represent a promising avenue for developing new antibiotics. However, the number of known natural AMPs with sufficient potency and low toxicity for use in veterinary and human medicine remains limited, hindering progress in this field. The urgent need for novel natural AMPs is evident. 

We propose for the first time that picobodies, a recently discovered class of peptides derived from natural cow antibodies, may possess potent antibacterial properties. Unlike conventional mammalian AMPs, picobodies exhibit exceptional diversity, owing to the unique nature of the bovine immune system. Additionally, all picobodies contain disulfide bonds that enable redox regulation of their activity, which distinguishes them from common antibiotics. We hypothesize that this redox activation allows picobodies to specifically target bacteria in infection sites characterized by a reducing environment, such as persistent bacterial biofilms. 

Our project, PicoBody, has four major objectives: (i) to interrogate natural picobody repertoires for antibacterial activity, (ii) to investigate whether cows can develop antibacterial picobodies targeting essential bacterial components, (iii) to understand how the redox environment influences the antibacterial activity of picobodies, and (iv) to evaluate the activity of antibacterial picobodies in both in vitro and in vivo models. 

To achieve these goals, we will employ a multidisciplinary approach that integrates protein science, molecular biology, microbiology, machine learning, and lab automation. This project aims to establish key methods for identifying antibacterial proteins, provide insights into the bovine immune system, validate picobodies as previously unknown natural AMPs, and open new research directions for the discovery of much-needed peptide antibiotics.