The World Health Organization cites multi-drug resistant (MDR) bacteria as one of the top three threats to human health. Unfortunately, antibiotic development has essentially ground to a halt thanks to these rapidly emerging resistant strains. No one wants to invest in a therapeutic with such a short shelf life. The need for a viable, broad treatment strategy is overwhelming. The only new classes of antibiotics introduced in the last twenty years are active solely against Gram-positive bacteria and resistance to these is already endemic. And that's the good news. Much worse, there have been no real advances in treating Gram- negative infections whatsoever. Clinicians have adopted the following mantra: "for the treatment of Gram- positives we need better drugs;for Gram-negatives we need any drugs". Without a deeper understanding of the bacterial resistance/persistence and transmission mechanisms, along with the development of new approaches to combat these MDR pathogens, countless people will die. Our studies have two aims. First, we would like to better understand the protective mechanisms that bacteria employ to overcome antibiotics and the host immune response. Second, we would like to impede these mechanisms using small molecule intervention. During the last funding period we elucidated functional processes and molecular recognition characteristics of proteins involved in a variety of bacterial responses, including biofilm formation and environmental sensing. These studies were aimed at identifying 'druggable'points in signal transduction pathways. As a result of these efforts, we were able to develop an arsenal of compounds (referred to as 2AIs) that re-sensitize MDR bacteria (both Gram-positive and Gram-negative) to current antibiotics. We have demonstrated the efficacy of these compounds against 20-plus bacterial strains. Here we will characterize a complete signaling pathway responsible for biofilm matrix production in order to determine sites for possible therapeutic intervention, elucidate the mechanism of action of our 2AI compounds, develop improved 2AI compounds and evaluate lead 2AIs to act as adjuvants to current antibiotics in an animal model.

Public Health Relevance

There is decreasing investment in antibiotic development because of the rapid increase in resistance to current antibiotics. It is not surprising that no on wants to develop new therapeutics that they believe will soon be useless. Such multi-drug resistance (MDR) will soon result in a worldwide infectious disease crisis. Here, we are addressing the MDR issue in two ways. First, by elucidating the detailed mechanisms by which pathogenic bacteria protect themselves - resulting in pathogenic infection, persistence and transmission. Second, by developing small molecule adjuvants that overcome these bacterial resistance traits such that MDR bacteria become susceptible to current antibiotics once again.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function B Study Section (MSFB)
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Flicker, Paula F
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North Carolina State University Raleigh
Schools of Earth Sciences/Natur
United States
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Tucker, Ashley T; Bobay, Benjamin G; Banse, Allison V et al. (2014) A DNA mimic: the structure and mechanism of action for the anti-repressor protein AbbA. J Mol Biol 426:1911-24
Bobay, Benjamin G; Thompson, Richele J; Milton, Debra L et al. (2014) Chemical shift assignments and secondary structure prediction of the phosphorelay protein VanU from Vibrio anguillarum. Biomol NMR Assign 8:177-9
Melander, Roberta J; Minvielle, Marine J; Melander, Christian (2014) Controlling bacterial behavior with indole-containing natural products and derivatives. Tetrahedron 70:6363-6372
Olson, Andrew L; Thompson, Richele J; Melander, Christian et al. (2014) Chemical shift assignments and secondary structure prediction of the C-terminal domain of the response regulator BfmR from Acinetobacter baumannii. Biomol NMR Assign 8:67-70
Olson, Andrew L; Tucker, Ashley T; Bobay, Benjamin G et al. (2014) Structure and DNA-binding traits of the transition state regulator AbrB. Structure 22:1650-6
Stowe, Sean D; Olson, Andrew L; Losick, Richard et al. (2014) Chemical shift assignments and secondary structure prediction of the master biofilm regulator, SinR, from Bacillus subtilis. Biomol NMR Assign 8:155-8
Blackledge, Meghan S; Worthington, Roberta J; Melander, Christian (2013) Biologically inspired strategies for combating bacterial biofilms. Curr Opin Pharmacol 13:699-706
Worthington, Roberta J; Melander, Christian (2013) Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol 31:177-84
Olson, Andrew L; Liu, Fan; Tucker, Ashley T et al. (2013) Chemical crosslinking and LC/MS analysis to determine protein domain orientation: application to AbrB. Biochem Biophys Res Commun 431:253-7
Blackledge, Meghan S; Melander, Christian (2013) Programmable DNA-binding small molecules. Bioorg Med Chem 21:6101-14

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