RESISTANCE TO BETA-LACTAM ANTIBIOTICS

Summary

Principal Investigator: SHAHRIAR contact MOBASHERY
Abstract: DESCRIPTION. Resistance to antibiotics is widespread among pathogenic bacteria and exacts a high cost on society. It is critically important that we develop strategies to prolong the clinical usefulness of the existing antibiotics. It is our view that the key to overcoming resistance to antibacterials is a full knowledge of the mechanisms of such resistance. This detailed knowledge should ultimately be instrumental in designing new antibiotics or redesigning old ones that circumvent the resistance problem in bacteria. A focus of this grant application is on the mechanism of resistance to beta-lactam antibiotics in Staphylococcus aureus, an important pathogen that has developed elaborate mechanisms for resistance by expressing both beta- lactamases, enzymes that hydrolytically destroy these antibiotics, or a penicillin-binding protein (PBP 2a) that is not readily inhibited by beta-lactam antibiotics. Three specific Aims are proposed. Specific Aim 1 is to study the process of interactions of beta-lactam antibiotics with the integral membrane protein BlaR1 of S. aureus. The beta-lactam sensor domain of this protein detects the presence of the antibiotic, a signal is transduced to the cytoplasm, where a protease domain of the protein is activated. The activated protease degrades (directly or indirectly) the represser for genes that manifest in expression of antibiotic resistance enzymes, the beta-lactamase and PBP 2a. The study for the full details of these processes is outlined. Specific Aim 2 proposes to investigate the properties of the beta-lactam sensor domain of a related protein, MecR1. The studies will delineate the mechanistic differences that are seen clinically in the onset of antibiotic resistance via this protein compared to the corresponding domain of BlaR1. Specific Aim 3 will follow up on the discovery in the Mobashery lab of a set of molecules that inhibit all three classes of serine- dependent beta-lactamases and also the BlaR1 protein. This type of enzyme inhibitor is expected to reverse the resistance phenotype in bacteria, rendering the the organisms susceptible to known beta-lactam antibiotics. RELEVANCE. Antibiotic resistance is a serious clinical problem with important societal cnsequences. The proposed work is to study how resistance to beta-lactam antibiotics has developed. The understanding of the mechanistic details should guide the way in devising strategies to circumvent the problem.
Funding Period: ----------------1992 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Three-dimensional structure of the bacterial cell wall peptidoglycan
    Samy O Meroueh
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556 5670, USA
    Proc Natl Acad Sci U S A 103:4404-9. 2006
  2. ncbi Why clinically used tazobactam and sulbactam are poor inhibitors of OXA-10 beta-lactamase: Raman crystallographic evidence
    Monica A Totir
    Departments of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Biochemistry 47:4094-101. 2008
  3. pmc Restoration of susceptibility of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics by acidic pH: role of penicillin-binding protein PBP 2a
    Sandrine Lemaire
    Unité de Pharmacologie Cellulaire et Moléculaire, Universite Catholique de Louvain, B 1200 Brussels, Belgium
    J Biol Chem 283:12769-76. 2008
  4. pmc Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus
    Leticia I Llarrull
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    Biochemistry 49:7975-7. 2010
  5. pmc Lysine Nzeta-decarboxylation switch and activation of the beta-lactam sensor domain of BlaR1 protein of methicillin-resistant Staphylococcus aureus
    Oleg Borbulevych
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 286:31466-72. 2011
  6. pmc Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance
    Leticia I Llarrull
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 286:38148-58. 2011
  7. pmc An amino acid position at crossroads of evolution of protein function: antibiotic sensor domain of BlaR1 protein from Staphylococcus aureus versus clasS D β-lactamases
    Malika Kumarasiri
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 287:8232-41. 2012

Detail Information

Publications7

  1. pmc Three-dimensional structure of the bacterial cell wall peptidoglycan
    Samy O Meroueh
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556 5670, USA
    Proc Natl Acad Sci U S A 103:4404-9. 2006
    ..The first two amino acids of the pentapeptide adopt a limited number of conformations. Based on this structure a model for the bacterial cell wall is proposed...
  2. ncbi Why clinically used tazobactam and sulbactam are poor inhibitors of OXA-10 beta-lactamase: Raman crystallographic evidence
    Monica A Totir
    Departments of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Biochemistry 47:4094-101. 2008
    ..These compounds lead to a single acyl-enzyme species, the presence of which was confirmed by Raman and MALDI-TOF experiments...
  3. pmc Restoration of susceptibility of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics by acidic pH: role of penicillin-binding protein PBP 2a
    Sandrine Lemaire
    Unité de Pharmacologie Cellulaire et Moléculaire, Universite Catholique de Louvain, B 1200 Brussels, Belgium
    J Biol Chem 283:12769-76. 2008
    ....
  4. pmc Binding of the gene repressor BlaI to the bla operon in methicillin-resistant Staphylococcus aureus
    Leticia I Llarrull
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    Biochemistry 49:7975-7. 2010
    ..These observations for the first time provide a quantitative picture of the processes that take place in the cytoplasm that lead to the induction of antibiotic resistance factors to counter the challenge by β-lactams...
  5. pmc Lysine Nzeta-decarboxylation switch and activation of the beta-lactam sensor domain of BlaR1 protein of methicillin-resistant Staphylococcus aureus
    Oleg Borbulevych
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 286:31466-72. 2011
    ..aureus...
  6. pmc Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance
    Leticia I Llarrull
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 286:38148-58. 2011
    ....
  7. pmc An amino acid position at crossroads of evolution of protein function: antibiotic sensor domain of BlaR1 protein from Staphylococcus aureus versus clasS D β-lactamases
    Malika Kumarasiri
    Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA
    J Biol Chem 287:8232-41. 2012
    ..These studies document how the nature of the residue at position 439 is critical for the fate of the protein in imparting unique functions on the same molecular template, to result in one as a receptor and in another as a catalyst...