As microbial drug-resistance increases, there is a critical need for new classes of compounds to combat infectious diseases. The Ixodes scapularis tick antifreeze glycoprotein, IAFGP, functions as an anti-infective agent against diverse bacteria including methicillin-resistant Staphylococcus aureus. Recombinant IAFGP and a peptide, PI, described herein and derived from this protein, bind to microbes and alter biofilm formation. Transgenic iafgp-expressing flies and mice challenged with bacteria, as well as wild-type animals administered IAFGP or PI, were resistant to infection, septic shock, or biofilm development on implanted biomaterials. Antifreeze protein controls bacterial infection and present new therapeutic strategies to counter pathogens.