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.
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.
|Schmidt, Nathan W; Agak, George W; Deshayes, Stephanie et al. (2015) Pentobra: A Potent Antibiotic with Multiple Layers of Selective Antimicrobial Mechanisms against Propionibacterium Acnes. J Invest Dermatol 135:1581-1589|
|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|
|Sgolastra, Federica; Deronde, Brittany M; Sarapas, Joel M et al. (2013) Designing mimics of membrane active proteins. Acc Chem Res 46:2977-87|
|Fu, Tsung-Hao; Li, Yan; Thaker, Hitesh D et al. (2013) Expedient Synthesis of SMAMPs via Click Chemistry. ACS Med Chem Lett 4:841-5|
|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|
|Schmidt, Nathan W; Wong, Gerard C L (2013) Antimicrobial peptides and induced membrane curvature: geometry, coordination chemistry, and molecular engineering. Curr Opin Solid State Mater Sci 17:151-163|
|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|
|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; Tai, Kenneth P; Kamdar, Karishma et al. (2012) Arginine in ?-defensins: differential effects on bactericidal activity correspond to geometry of membrane curvature generation and peptide-lipid phase behavior. J Biol Chem 287:21866-72|
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