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
- Low solubility
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.
Recent Publications:
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):905-17 doi 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 PubMed PMC
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
