Novel Compounds Targeting Bacterial PBPs

Summary

Principal Investigator: LUIGI XERRI
Abstract: DESCRIPTION (provided by applicant): This Phase I SBIR Application centers on a new class of non-??-lactam antibacterial agents that target the same biological target as the ?-lactam class of antibiotics (i.e., the Penicillin Binding Proteins, or PBPs), but with the prospect of avoiding n important determinant of cross-resistance to ?-lactams. We have identified a novel series of highly selective, non-cytotoxic small molecule lead compounds that bind to and disrupt PBP function in both gram-positive and gram-negative bacteria. Preliminary data show that this new series, exemplified by prototype lead compound PBP-539, is chemically impervious to ?-lactamase degradation, a dominant resistance determinant for all ?-lactams, and one that is growing at an alarming rate. This lead prototype shows good anti-bacterial activity against core gram positives (S. aureus and S. pneumoniae) and both wild-type and ESBL-expressing gram negatives in the Enterobacteriaceae family (E. coli and K. pneumoniae). In addition, the early leads have good aqueous solubility (>1 mg/mL), low protein binding (<50% in mouse, dog, and human serum), high selectivity vs. mammalian serine-based enzymes (IC50 vs. 6 different mammalian serine proteases >100 ?M), and are not cytotoxic to mammalian cells (CC50 >256 ?g/mL for 3 cell lines). During the 2-year timeframe of the Application, we intend to advance the chemical optimization of this series to an "Advanced Lead" stage (a key milestone in drug discovery between Lead identification and Preclinical Candidate selection). This will involve: (a) improving potency levels across core pathogens (S. aureus, S. pneumoniae, ESBL-producing Enterobacteriaceae);and (b) demonstrating in vivo proof of concept efficacy in a murine model of bacterial infection. Success would trigger submission of a Phase II grant proposal wherein a second phase of Lead Optimization (Late Stage) would be performed directed at delivering a 1st Preclinical Candidate. Ultimately, it is envisioned that this new class of cell wall synthesis inhibitors may serve as a platform for a portfolio of products with different coverage spectra and modes of administration. Such new products could serve as a critical advance in the search for new treatments for serious multi-resistant bacterial infections in the nosocomial and community settings.
Funding Period: 2012-06-21 - 2014-05-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Inhibitors of Staphylococcus aureus NaMN adenylyltransferase NadD
    Andrei L Osterman; Fiscal Year: 2013
    ..Selected best inhibitors will be used in future work as molecular probes to further explore NAD biosynthesis as a target pathway for the development of novel antibiotics. ..
  2. Development of a Novel PolC Inhibitor as a Gram-Positive Antibiotic
    THALE CROSS JARVIS; Fiscal Year: 2013
    ..This project represents a compelling opportunity to combat the rising tide of antibiotic-resistant infections, providing a much-needed public health benefit. ..
  3. Compounds to treat Helicobacter pylori infection
    Kenneth Coleman; Fiscal Year: 2013
    ..However, currently available therapeutics are broad spectrum antibiotics, which cause high levels of resistance and unwanted side-effects. We will develop an antibiotic that specifically targets H. pylori. ..
  4. Targeting superbugs: discovery and development of new broad-spectrum lipopeptides
    Jian Li; Fiscal Year: 2013
    ..aeruginosa, A. baumannii and K. pneumoniae. Overall, this project targets the urgent global unmet medical need and responds in a timely manner to the recent global call for discovery of new antibiotics: The 10 x '20 Initiative. ..
  5. Pediatric toxicity and efficacy in long-term systemic treatment with anti-sense
    JOHANNES NICOLAAS VAN DEN ANKER; Fiscal Year: 2013
    ..A kidney toxicology assessment core supports these projects. ..
  6. Oklahoma Center for Respiratory and Infectious Diseases
    Lin Liu; Fiscal Year: 2013
    ..The completion of the goals of the present COBRE will have a major impact on research programs on respiratory infectious diseases in the State of Oklahoma. ..
  7. Elucidating beta-lactamase functional mechanisms via evolutionary conservation
    Dennis R Livesay; Fiscal Year: 2013
    ..As such, we propose a series of additional studies along these lines to expand our understanding of BL structure and function, potentially paving the way to new therapeutic opportunities. ..
  8. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  9. Optimization of novel pyranopyridine efflux pump inhibitors
    Son Truong Nguyen; Fiscal Year: 2013
    ..Aim 3. Prioritize analogs using in vitro cytotoxicity and ADME assays. Aim 4. Verify the mechanism of action and identify the molecular target of the MBX-2319 series of efflux pump inhibitors. ..
  10. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
  11. Targeting MraY: Synthesis and Validation of MraY Inhibitors
    Michio Kurosu; Fiscal Year: 2013
    ..Clinical responses of MDR- TB patient to currently available drugs have been poor, and in some cases there is no response at all. The long term goal of this grant submission is to develop new drug leads for MDR-TB. ..
  12. The use of mass spectrometry for rapid detection of carbapenemase-producing bacte
    DAVID RYAN PEAPER; Fiscal Year: 2013
    ..Future phases of development will apply the technology to primary specimens, which will be followed by multicenter clinical trials in pursuit o FDA 510(k) clearance of the final product. ..
  13. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  14. Molecular Archaeology: Vintage Beta Lactams for Resistant Gram Negative Infectio
    Marvin J Miller; Fiscal Year: 2013
    ..Conduct in vitro toxicology battery and pilot toxicology studies. Aim 5. Conduct 14-day range-finding toxicology studies. Upon successful completion of this project, we will be ready to proceed into IND-enabling toxicology studies. ..
  15. Optimization of Neoglycoside Antibiotics for Nosocomial Pathogens and Select Agen
    Arnold Louie; Fiscal Year: 2013
    ....
  16. Discovery of Polymyxin-based Antibacterial Agents Active Against Multi-Drug Resis
    Lawrence H Lash; Fiscal Year: 2013
    ..This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation. ..
  17. Cell wall synthesis enzymes and beta-lactam resistance in Enterococcus faecium
    Louis B Rice; Fiscal Year: 2013
    ..They will also enhance our understanding of cell wall synthesis mechanisms in Gram-positive cocci and reveal promising new targets for antibacterial therapy. ..
  18. Challenges in beta-Lactamase Mediated Resistance
    Robert A Bonomo; Fiscal Year: 2013
    ..We chose these [unreadable]-lactamases as they are among the most important class A and class C enzymes in Gram-negative bacteria. ..