1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
2. Harvard–MIT Health Sciences and Technology, Cambridge, Massachusetts 02139, USA
3. Agrivida, 411 Massachusetts Ave B1, Cambridge, Massachusetts 02139, USA
4. IBM Research Division, Thomas J.Watson Research Center, Yorktown Heights, New York 10598, USA
5. These authors contributed equally to this work.

Correspondence to: Gregory Stephanopoulos¹ Correspondence and requests for materials should be addressed to G.S. (Email: gregstep@mit.edu).

Abstract

Antimicrobial peptides (AmPs) are small proteins that are used by the innate immune system to combat bacterial infection in multicellular eukaryotes¹. There is mounting evidence that these peptides are less susceptible to bacterial resistance than traditional antibiotics and could form the basis for a new class of therapeutic agents². Here we report the rational design of new AmPs that show limited homology to naturally occurring proteins but have strong bacteriostatic activity against several species of bacteria, including Staphylococcus aureus and Bacillus anthracis. These peptides were designed using a linguistic model of natural AmPs: we treated the amino-acid sequences of natural AmPs as a formal language and built a set of regular grammars to describe this language. We used this set of grammars to create new, unnatural AmP sequences. Our peptides conform to the formal syntax of natural antimicrobial peptides but populate a previously unexplored region of protein sequence space.

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