Project Title: Therapeutics for Drug-Resistant Bacetria: Arylpropionyl Phloroglucinols

Project Summary:

In preliminary work, we have identified a novel class of broad-spectrum antibacetrial agents: arylpropionyl phloroglucinols (APPs).  APPs potently inhibit bacetrial RNA polymerase (RNAP)--but not mammalian RNAP--in vitro, potently inhibit bacetrial growth in culture, and potently clear infection in a mouse model of methicillin-resistant Staphylococcus aureus infection.  APPs exhibit antibacetrial activity against both    Gram-positive and Gram-negative bacetrial pathogens, including drug-sensitive, beta-lactam-resistant, macrolide-resistant, tetracycline-resistant, rifampin-resistant, vancomycin-resistant, and multi-drug-resistant Staphylococcus aureus, Enterococcus faecalis, NIAID category A pathogen Bacillus anthracis, NIAID category A pathogen Francisella tularensis, and NIAID category B pathogen Brucella melitensis.  APPs exhibit no cross-resistance with rifampin, the RNAP inhibitor in current use in broad-spectrum antibacetrial therapy, and exhibit a spontaneous resistance rate <1/10 that of rifampin.  APP concentrations that inhibit bacetria growth in culture are not cytotoxic to mammalian cells in culture, and APPs do not exhibit acute toxicity in mice upon subcutaneous administration at doses up to 100 mg/kg.

We provisionally have defined the binding site on RNAP for APPs and the mechanism of inhibition of RNAP by APPs.  The binding site and mechanism have no overlap with the binding site and mechanism of the RNAP inhibitor rifampin, consistent with the absence of cross-resistance with rifampin. 

We have constructed provisional structural models of RNAP-APP complexes, and we have defined provisional structure-activity relationships for APPs.  The structural models and structure-activity relationships suggest changes that could be made to APPs to improve potency and properties. 

APPs can be synthesized in just one or two steps.  The simple synthetic procedures enable straightforward preparation of APP analogs.

We propose to leverage the structural models, structure-activity relationships, and synthetic procedures from preliminary work in order to design, synthesize, and evaluate APP analogs having increased efficacy.

Biography: 

Richard H. Ebright, Ph.D., is Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University and Laboratory Director at the Waksman Institute of Microbiology.  He directs a laboratory of approximately twenty postdoctoral associates, graduate students, and technicians and serves as project leader on four National Institutes of Health research grants ("Bacetrial Transcription Complexes," "Therapeutics for Drug-Resistant Bacetria: Myxopyronins," "Therapeutics for Drug‑Resistant Bacetria: Pseudouridimycins," and "Therapeutics for Drug-Resistant Bacetria: Arylpropionyl Phloroglucinols") and a Global Alliance for TB Drug Development contract ("Therapeutics for Tuberculosis: Mycobacetrial RNAP Inhibitors").

His research focusses on the structure, mechanism, and regulation of bacetrial transcription complexes, and on the development of inhibitors of bacetrial transcription as antituberculosis agents and broad-‑spectrum antibacetrial agents.  His research employs tools of structural biology, biophysics, and drug-discovery.

He received his A.B. (Biology, summa cum laude) and Ph.D. (Microbiology and Molecular Genetics) degrees from Harvard University.  He performed graduate research at Harvard and the Institut Pasteur and was a Junior Fellow of the Harvard University Society of Fellows.  In 1987, he was appointed as a Laboratory Director at the Waksman Institute and a faculty member at Rutgers University.  From 1997 to 2013, he was co-appointed as an Investigator of the Howard Hughes Medical Institute. 

He has received the Searle Scholar Award, the Walter J. Johnson Prize, the Schering-Plough Award of the American Society for Biochemistry and Molecular Biology, the Waksman Award of the Theobold Smith Society, and the MERIT Award of the National Institutes of Health.  He is a Fellow of the American Association for Advancement of Science, the American Academy of Microbiology, and the Infectious Diseases Society of America.

He has more than one hundred thirty publications in peer-reviewed journals and more than thirty issued and pending patents.  He has been an invited participant and presenter at scientific meetings in the US and overseas.

He served for sixteen years as editor of the Journal of Molecular Biology.  He has served on the NIH Molecular Biology Study Section and on NIH special emphasis panels.  He is a member of the Institutional Biosafety Committee of Rutgers University and has been a member of the Working Group on Pathogen Security of the state of New Jersey and the Controlling Dangerous Pathogens Project of the Center for International Security Studies.

Contact info:

Richard H. Ebright
Waksman Institute, Rutgers University, Piscataway NJ 08854
PH: 848-445-5179; FAX: 732-445-5735
ebright@waksman.rutgers.edu
https://www.waksman.rutgers.edu/ebright/home