Leticia I. Llarrull, Ph.D.

Research

The Gram-positive bacteria Staphylococcus aureus is the main cause of hospital- and community-associated infections. S. aureus is the most frequent cause of surgical, lower respiratory tract, and cardiovascular infections. In addition, it is the second most common cause of health-care associated pneumonia and of bloodstream infections.Methicillin-resistant S. aureus (MRSA) is a high priority concern in the world and in particular in Latin America, both in hospitals and in the community. MRSA has become the first cause of hospital-associated infections in Latin America, and there has been an increasing number of reports of community acquired MRSA infections. The acquisition of resistance to beta-lactam antibiotics, generally concurrent with the acquisition of resistance to other antibacterial agents, represents a huge challenge for the prevention and treatment of S. aureus associated infections. Very few new antibacterials are in advanced stages of clinical evaluation for the treatment of bacterial infections, including MRSA. S. aureus presents two main mechanisms of resistance to beta-lactam antibiotics: the expression of the PC1 beta-lactamase, capable of hydrolyzing and inactivating the beta-lactam antibiotics, and the acquisition of a PBP (PBP2a) with low affinity for beta-lactam antibiotics, and which is hence not inhibited by them. The genes that code for these proteins in S. aureus are part of operons. Each one of these operons is composed of three genes, one gene that codes for the effector protein (PC1 beta-lactamase or PBP2a, respectively), a sensor membrane protein (BlaR1 and MecR1, respectively), and a repressor protein that binds to the operator region (BlaI and MecI, respectively). S. aureus presents another important system that coordinates the response to antibiotics that inhibit the biosynthesis of the peptidoglycan: the VraSR system. This two-component system rapidly detects the stress in the cell wall and transmits the signal to the cytoplasm. Inactivation of the VraSR system drastically affects the resistance of different S. aureus strains to vancomycin (a glycopeptide antibiotic) and to beta-lactam antibiotics. It has been proposed that the VraSR system would sense the reduction in the peptide linkages between adjacent glycan strands as a consequence of the inhibitory effect of these antibiotics. However, the signal detected by the extracellular region of the sensor protein VraS has not been identified yet, and some related systems have been shown to interact directly with antibiotics. The three systems here described have important roles in resistance to cell-wall active antibiotics, but the details of the molecular mechanisms involved in signal transduction have not been completely unveiled yet. Understanding the signal transduction pathway in these systems is of great interest since the sensor proteins are possible targets for the design of inhibitors that can be used in combination therapies with beta-lactam and glycopeptide antibiotics. My main research interest is the elucidation of the signal transduction pathways of these systems, and in particular how is the presence of the cell-wall active antibiotic sensed by the membrane proteins, and the elucidation of the topology and structure of these membrane proteins.