We are facing a growing threat from infectious organisms that are becoming resistant to even the most recently developed antibiotics that target essential steps in cell wall assembly and protein biosynthesis. To combat this threat we need a broader approach to antimicrobial development that identifies novel targets with different modes of action, thereby leading to new classes of drugs. Our long term goal of this research program is to identify and examine key enzymes selected from essential microbial pathways that can potentially serve as novel drug targets. The objective for this research proposal is to use our extensive knowledge of the core enzymes in the essential microbial aspartame pathway as a guide for the development of effective lead compounds. It is our hypothesis that the aspartame 2-semialdehyde dehydrogenises of these infectious organisms are attractive and untested targets for novel drug intervention, and that selective inhibitors of this core enzyme will lead to the development of new classes of antimicrobials that will be highly effective against the growing threat from multidrug resistant infectious organisms. This hypothesis will be testing by the following specific aims: 1) modify the initial ASA dehydrogenate inhibitors to develop advanced lead compounds;2) combine new inhibitor fragments to produce potent and selective inhibitors;and 3) develop species-specific inhibitors against ASA dehydrogenises from selected pathogenic organisms. The innovation of our proposed work is the exploration of new paradigms for antibiotic development. Our plan is to select unique microbial pathways which produce a variety of essential products that function in a wide range of critical phases of microbial development. Shutting down these pathways in their early stage with potent and selective inhibitors will cause a myriad of problems that the organism must try to overcome if it is to survive. A second innovative aspect of our approach challenges the existing paradigm of exclusively targeting the development of broad spectrum antibiotics. As an outcome of the proposed studies we expect to identify several validated lead compounds that target this key metabolic enzyme of the aspartame pathway with high affinity and improved selectivity. Developing advanced lead compounds with specificity against selected pathogenic organisms will provide added value to these drug candidates. This proposed research is significant because achievement of these specific aims will help to validate an expanded paradigm for antibiotic targeting and encourage a broader view of drug development.

Public Health Relevance

The microbial threat to human health is growing due to the dramatic increase in the number of infectious organisms that have evolved to become resistant to many of the available clinical antibiotics. As a consequence, the decreasing number of effective antibiotics available to treat these infections and the dearth of drug candidates with novel mechanisms of action has lent a greater urgency to the search for new antibiotics against novel microbial targets.

National Institute of Health (NIH)
Research Project (R01)
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Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
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Xu, Zuoyu
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University of Toledo
Schools of Arts and Sciences
United States
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Thangavelu, Bharani; Pavlovsky, Alexander G; Viola, Ronald (2014) Structure of homoserine O-acetyltransferase from Staphylococcus aureus: the first Gram-positive ortholog structure. Acta Crystallogr F Struct Biol Commun 70:1340-5
Pavlovsky, Alexander G; Liu, Xuying; Faehnle, Christopher R et al. (2012) Structural characterization of inhibitors with selectivity against members of a homologous enzyme family. Chem Biol Drug Des 79:128-36
Luniwal, Amarjit; Wang, Lin; Pavlovsky, Alexander et al. (2012) Molecular docking and enzymatic evaluation to identify selective inhibitors of aspartate semialdehyde dehydrogenase. Bioorg Med Chem 20:2950-6
Sarver, Jeffrey G; Trendel, Jill A; Bearss, Nicole R et al. (2012) Early stage efficacy and toxicology screening for antibiotics and enzyme inhibitors. J Biomol Screen 17:673-82
Tawfik, Dan S; Viola, Ronald E (2011) Arsenate replacing phosphate: alternative life chemistries and ion promiscuity. Biochemistry 50:1128-34
Gao, Geng; Liu, Xuying; Pavlovsky, Alexander et al. (2010) Identification of selective enzyme inhibitors by fragment library screening. J Biomol Screen 15:1042-50