Membrane-disrupting antimicrobial peptides (AMPs) have long been considered possible alternate therapeutics for the fight against drug-resistant bacteria. Yet, development of AMPs into drugs is almost absent.
We have quantified some of the major impediments to systemic clinical utility of AMPs:
•Rapid degradation by plasma proteases
•Rapid degradation by cytosolic proteases
•Inhibition due to host cell binding
•Residual cell lysis and toxicity
We are doing two things to solve the problem. 1) We are characterizing these impediments for a better understanding, and 2) We are using the knowledge to enable synthetic molecular evolution of novel AMPs that simultaneously avoid all of the impediments to clinically useful activity.
Starr CG, He J, Wimley WC. Host Cell Interactions Are a Significant Barrier to the Clinical Utility of Peptide Antibiotics. ACS Chem Biol. 2016 Dec 16;11(12):3391-3399. doi PubMed
He J, Starr CG, Wimley WC. A lack of synergy between membrane-permeabilizing cationic antimicrobial peptides and conventional antibiotics. Biochim Biophys Acta. 2015 Jan;1848(1 Pt A):8-15. doi PubMed PMC
He J, Krauson AJ, Wimley WC. Toward the de novo design of antimicrobial peptides: Lack of correlation between peptide permeabilization of lipid vesicles and antimicrobial, cytolytic, or cytotoxic activity in living cells. Biopolymers. 2014 Jan;102(1):1-6. doi. PubMed PMC
Walkenhorst WF, Klein JW, Vo P, Wimley WC. pH Dependence of microbe sterilization by cationic antimicrobial peptides. Antimicrob Agents Chemother. 2013 Jul;57(7):3312-20. doi PubMed PMC.
Wimley WC. (2010) Describing the mechanism of antimicrobial peptide action with the interfacial activity model. ACS Chem Biol. 2010 Oct 15;5(10):905-17doi PubMed PMC
Rathinakumar R, Wimley WC. (2010) High-throughput discovery of broad-spectrum peptide antibiotics. FASEB J. 2010 Sep;24(9):3232-8. doi PubMed PMC
Wimley WC, Hristova K. Antimicrobial peptides: successes, challenges and unanswered questions. J Membr Biol. 2011 Jan;239(1-2):27-34. doi. PubMed PMC (Collaboration with the Hristova Lab at Johns Hopkins)
Rathinakumar R, Walkenhorst WF, Wimley WC. (2009) Broad-spectrum antimicrobial peptides by rational combinatorial design and high-throughput screening: the importance of interfacial activity. J Am Chem Soc. 2009 Jun 10;131(22):7609-17 doi PubMedPMC
Rathinakumar R, Wimley WC. (2008) Biomolecular engineering by combinatorial design and high-throughput screening: small, soluble peptides that permeabilize membranes. J Am Chem Soc. 2008 Jul 30;130(30):9849-58. doi PubMed PMC