As fewer and fewer small-molecule antibiotics remain effective against drug-resistant bacteria, some researchers are turning to antibacterial enzymes to combat resilient infections. But many of these large-molecule drug candidates are intercepted by the host’s immune system before they can cure the illness. Now, researchers at Dartmouth College led by protein engineer Karl E. Griswold have shown that an engineered variant of one such enzyme, lysostaphin, may treat methicillin-resistant Staphylococcus aureus (MRSA) infections more effectively than a nonengineered version (Chem. Biol. 2015, DOI: 10.1016/j.chembiol.2015.04.017). The group deimmunized lysostaphin by first using a predictive algorithm to identify the protein’s T-cell epitopes—regions of the enzyme that the immune system recognizes. These epitopes would bind to a cell receptor coded for by a specific HLA allele. The researchers then screened a library of epitope-depleted lysostaphin variants to identify a candidate that would have low immunogenicity but still maintain the protein’s powerful lysing function. Genetically humanized mice given the screen’s best result, dubbed Lib5, were more likely to survive a MRSA infection than those given wild-type lysostaphin. The next step, Griswold says, will be to completely deimmunize lysostaphin against multiple HLA alleles.