The broad, overall objectives of this work are to use NMR, X-ray and computational methods to help develop novel anti-bacterial agents, which enhance innate immune system based killing, in addition to killing bacteria directly.
The First Aim i s to develop molecules that inhibit formation of the orange carotenoid virulence factor, staphyloxanthin, in Staphylococcus aureus. In recent work, we discovered that human squalene synthase inhibitors can also block staphyloxanthin biosynthesis in S. aureus, at 200 nM levels. The resulting S. aureus (L. aureus=golden) are white, non-infective in mice and are killed by neutrophils, since they have decreased defenses to reactive oxygen species.
In Aim 1, we will develop more effective compounds, using NMR, X-ray and QSAR results to guide the design process. If successful, this work would be of importance given the increasing number S. aureus strains that are becoming resistant to conventional antibiotics.
The Second Aim i s to develop the azole class of molecules currently used as anti-fungals, as agents against S. aureus, blocking bacterial flavohemoglobin dioxygenase (which detoxifies NO from innate immune cells), as well as affecting isoprenoid biosynthesis. We will first investigate how azoles bind to flavohemoglobin and deduce structure-activity relationships that will guide the design of other, more potent inhibitors. Second, we will investigate how azoles exert their direct anti-bacterial activity. We propose to test the hypothesis that this activity is a result of the inhibition of isoprenoid biosynthesis, by correlating isoprenoid levels with anti-bacterial activity, and by using microarray techniques to investigate the bacterial transcriptome. If successful, this work would lead to novel azoles that inhibit bacterial defenses against NO-based killing, as well as new compounds that inhibit bacterial cell wall biosynthesis.
The Third Aim i s to develop bisphosphonates that activate ?? T cells of the innate immune system to kill bacteria, in addition to developing novel bisphosphonates that kill bacteria directly. In each Aim, we will use the strategy of developing alternate uses for existing types of drugs already used or tested in humans: cholesterol lowering drugs that block virulence in S. aureus (Aim 1), anti-fungal azoles with anti- bacterial activity (Aim 2) and bone resorption drugs that have immunomodulation or direct anti- bacterial activity (Aim 3).In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information.
The research proposed is designed to lead to new approaches to treating infectious diseases. Particular emphasis will be given to developing alternate, novel uses for existing types of drugs: cholesterol lowering molecules that also block Staph infections;anti-fungals with anti-bacterial activity, and bone resorption drugs that stimulate the immune system as well as kill bacteria directly.
|Oldfield, Eric; Feng, Xinxin (2014) Resistance-resistant antibiotics. Trends Pharmacol Sci 35:664-74|
|Ren, Feifei; Feng, Xinxin; Ko, Tzu-Ping et al. (2013) Insights into TIM-barrel prenyl transferase mechanisms: crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus. Chembiochem 14:195-9|
|Zhu, Wei; Zhang, Yonghui; Sinko, William et al. (2013) Antibacterial drug leads targeting isoprenoid biosynthesis. Proc Natl Acad Sci U S A 110:123-8|
|Ziniel, Peter D; Desai, Janish; Cass, Cynthia L et al. (2013) Characterization of potential drug targets farnesyl diphosphate synthase and geranylgeranyl diphosphate synthase in Schistosoma mansoni. Antimicrob Agents Chemother 57:5969-76|
|Zhang, Yonghui; Zhu, Wei; Liu, Yi-Liang et al. (2013) Chemo-Immunotherapeutic Anti-Malarials Targeting Isoprenoid Biosynthesis. ACS Med Chem Lett 4:423-427|
|Lin, Fu-Yang; Zhang, Yonghui; Hensler, Mary et al. (2012) Dual dehydrosqualene/squalene synthase inhibitors: leads for innate immune system-based therapeutics. ChemMedChem 7:561-4|
|Lin, Fu-Yang; Liu, Yi-Liang; Li, Kai et al. (2012) Head-to-head prenyl tranferases: anti-infective drug targets. J Med Chem 55:4367-72|
|Oldfield, Eric; Lin, Fu-Yang (2012) Terpene biosynthesis: modularity rules. Angew Chem Int Ed Engl 51:1124-37|
|Wang, Hong; Sarikonda, Ghanashyam; Puan, Kia-Joo et al. (2011) Indirect stimulation of human Výý2Výý2 T cells through alterations in isoprenoid metabolism. J Immunol 187:5099-113|
|Durrant, Jacob D; Cao, Rong; Gorfe, Alemayehu A et al. (2011) Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design. Chem Biol Drug Des 78:323-32|
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