To address the pressing need for broad spectrum, novel antibiotics, we will build on important preliminary results to design and optimize AMOs against food-borne pathogens, importantly expanding the scope of previous results to treat Gram-negative organisms. To this end, we have identified three molecular scaffolds with good preliminary activity and these will be further developed The fundamental mechanism for antibacterial activity including the role of the membranes and membrane components, the ability or inability of bacteria to develop resistance to these new AMOs and the role these AMOs play on the innate and/or adaptive immune system will be determined. The goal is to identify compounds, or compound classes, that demonstrate potent antibacterial in vivo efficacy against Category B food-borne pathogens without obvious toxicity. Acute toxicity, pharmacokinetic properties, metabolic stability and in vivo efficacy of the lead compounds will be evaluated. The results from these studies will be used to select a lead compound for complete drug development evaluations suitable for regulatory submission. The ultimate goal of the program is to complete all studies necessary to enable IND filing. Based on our previous experience in which we translated an AMO from initial discovery to an approved Canadian CTA in 5 years, the proposed schedule is reasonable and appropriate.

Public Health Relevance

The need for new antibiotics is pressing and developing broad spectrum agents is a key initiative of NIAID. Our novel approach to identifying leads which capture the antimicrobial activity of natural antimicrobial peptides has already inability on CTA approval. Here the focus is on Gram-negative organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI082192-05
Application #
8500126
Study Section
Special Emphasis Panel (ZAI1-MMT-M (J3))
Program Officer
Mills, Melody
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$1,122,024
Indirect Cost
$161,927
Name
University of Massachusetts Amherst
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
Lee, Michelle W; Chakraborty, Saswata; Schmidt, Nathan W et al. (2014) Two interdependent mechanisms of antimicrobial activity allow for efficient killing in nylon-3-based polymeric mimics of innate immunity peptides. Biochim Biophys Acta 1838:2269-79
Schmidt, Nathan W; Deshayes, Stephanie; Hawker, Sinead et al. (2014) Engineering persister-specific antibiotics with synergistic antimicrobial functions. ACS Nano 8:8786-93
Schmidt, Nathan W; Mishra, Abhijit; Wang, Jun et al. (2013) Influenza virus A M2 protein generates negative Gaussian membrane curvature necessary for budding and scission. J Am Chem Soc 135:13710-9
Hu, Kan; Schmidt, Nathan W; Zhu, Rui et al. (2013) A critical evaluation of random copolymer mimesis of homogeneous antimicrobial peptides. Macromolecules 46:1908-1915
Thaker, Hitesh D; Cankaya, Alper; Scott, Richard W et al. (2013) Role of Amphiphilicity in the Design of Synthetic Mimics of Antimicrobial Peptides with Gram-negative Activity. ACS Med Chem Lett 4:481-485
Schmidt, Nathan W; Mishra, Abhijit; Lai, Ghee Hwee et al. (2011) Criterion for amino acid composition of defensins and antimicrobial peptides based on geometry of membrane destabilization. J Am Chem Soc 133:6720-7
Thaker, Hitesh D; Sgolastra, Federica; Clements, Dylan et al. (2011) Synthetic mimics of antimicrobial peptides from triaryl scaffolds. J Med Chem 54:2241-54
Zasloff, Michael; Adams, A Paige; Beckerman, Bernard et al. (2011) Squalamine as a broad-spectrum systemic antiviral agent with therapeutic potential. Proc Natl Acad Sci U S A 108:15978-83
Mishra, Abhijit; Lai, Ghee Hwee; Schmidt, Nathan W et al. (2011) Translocation of HIV TAT peptide and analogues induced by multiplexed membrane and cytoskeletal interactions. Proc Natl Acad Sci U S A 108:16883-8
Mishra, Abhijit; Tai, Kenneth P; Schmidt, Nathan W et al. (2011) Small-angle X-ray scattering studies of peptide-lipid interactions using the mouse paneth cell ýý-defensin cryptdin-4. Methods Enzymol 492:127-49