Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Targeting “Beta lactamase-C” in development of novel anti-tuberculosis therapeutics
Tuberculosis is a common, and in many cases lethal, infectious disease caused by various strains of Mycobacterium, usually Mycobacterium tuberculosis. (Kumar, V., Abbas, A. K., Fausto, N., Mitchell, R.N., 2007) In addition, co-infection with Mycobacterium tuberculosis and HIV (TB/HIV), especially in Africa, and multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in all regions, (WHO, 2010) makes it important to develop novel therapeutics against this bacterium. Penicillin like β-Lactam antibiotics are among the most clinically prescribed drugs for antibacterial therapeutics. The general mechanism of action involved the inhibition of enzyme d,d-transpeptidases, which takes part in the biosynthesis of the bacterial cell wall.(Heesemann J., 1993) A major strategy of bacterial resistance to β-lactams is the production of β-lactamases that catalyze the hydrolysis of β-lactams, leading to the inactivation of the antibiotics. β-Lactams have not been used in clinical practice to treat TB infections, because an active penicillinase was reported in M. tuberculosis.( Lessel, J., 1996) BlaC is a class A β-lactamase that contains a nucleophilic serine residue (Ser70) and shares sequence homology with the penicillin-binding protein (PBP) domain of the ancestral d,d-transpeptidases.
Recent studies’ including our lab shows that, β-lactam drugs like Clavulanate, Carbapenem, Meropenem are used primarily against this type of resistant bacteria (Hugonnet, J. E., Tremblay, L. W., Boshoff, H. I., Barry, C. E. 3rd, Blanchard, J. S., 2009). β-lactamase induces the same acetylating reaction with all of these drugs but can’t induce deacetylation. As a result, those drugs remain attached with β-lactamase even after the distortion of their β-lactam ring. At this time, secondary treatment has been done by applying previously used potent penicillin like β-lactam drugs with this primarily treated β-lactamase. In current study, we conducted kinetic and mass spectrometric analysis of different BlaC inhibitors, like NXL104 (Xu, H., Hazra, S., Blanchard, J. S., 2012) and showed that how they quantitatively inactivates BlaC by forming a carbamyl linkage with the enzyme. In addition, we determined the three-dimensional structures of the different reactive forms of these drugs for better understanding the undergoing mechanisms involved in this inhibition process. Based on our understanding we are trying to develop novel small molecules with better inhibitory process.
Hugonnet, J. E., Tremblay, L. W., Boshoff, H. I., Barry, C. E. 3rd, Blanchard, J. S. (2009). Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science, 323:1215-1218.
Kumar, V., Abbas, A. K., Fausto, N., Mitchell, R.N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. 516–522.
Lessel, J. (1996). Penicillin--binding protein: the target for beta-lactam antibiotics, beta-lactamases and their inhibitors. Pharm Unserer Zeit, 25:17-27.
WHO. (2010). Multidrug and extensively drug-resistant TB (M/XDR-TB): 2010 global report on surveillance and response.
Department of Biochemistry