Protein engineering for the development of novel antimicrobial agents

PROJECT SUMMARY
Antimicrobial resistance increasingly threatens our ability to effectively treat a wide range of infections. Absent
the development of novel antibiotics, humanity faces the prospect of a return to the pre-antibiotic era with
associated mortality to rival that of cancer. One promising approach for the development of novel antibiotics is
the engineering of antimicrobial peptides (AMPs), miniproteins of diverse structural classes made by all
branches of life to defend against microbes. In particular, the engineering of human AMPs presents the
opportunity to leverage both the antimicrobial and immunomodulatory properties of these AMPs to treat
infections. Under the guidance of mentors at the Massachusetts Institute of Technology (MIT), Massachusetts
General Hospital (MGH), and the Broad Institute, the candidate has adapted fast flow chemistry for the rapid
synthesis and engineering of human AMPs, and in this proposal he seeks to extend these efforts through two
aims. Aim 1 defines the structure-activity relationships underlying the mechanisms of gram-negative killing and
phagocyte chemotaxis mediated by three human AMPs of distinct structural types, while Aim 2 extends these
lines of inquiry to the development of derivatives of LL-37 as lead therapeutics. Together, these aims lay the
groundwork for extension of the studies described to additional facets of AMP biology and engineering as well
as preclinical applications as the candidate transitions to independence.
The candidate’s research background consists of doctoral training in innate immunology against retroviral
infection combined with clinical training in infectious diseases. This proposal for a K08 Mentored Clinical
Scientist Research Career Development Award will enable the candidate to complete additional hands-on and
didactic training in protein engineering and omics technologies over a five-year period toward the goal of
establishing an independent, R01-funded research program applying these approaches to the ongoing study
and development of human AMPs as novel antibiotics. In this effort, he is guided by primary mentors with
expertise in protein engineering and mass spectrometry as well as bacterial pathogenesis and genomic
technologies, which is further supported by an advisory board with deep expertise in microbiology,
immunology, proteomics, AMP mechanisms of action, and drug development as well as the extensive
resources of MIT, MGH, and the Broad Institute.

Grant Number: 5K08AI166345-04
NIH Institute/Center: NIH
Principal Investigator: John Albin