In Silico-Mediated Virtual Screening and Molecular Docking Platforms for Discovery of Non β-Lactam Inhibitors of Y-49 β-Lactamase from Mycobacterium Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a worldwide health concern. The world health organization in its 2017 tuberculosis report states, “TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS” [1-3]. The failure to control TB is due to the emergence of Mtb strains that are resistant to first line beta lactam antibiotics, because of overuse. One of the most effective resistance mechanisms to β-lactam antibiotics involves the production of β-lactamases which cleave the amide bond in the target β-lactam ring hydrolyzing the drug before it reaches its target. The beta-lactamases are classified into four classes: A, B, C and D. These classes are based on conserved and distinguishing amino acid motifs [1-3]. Classes A, C, and D include enzymes that hydrolyze their substrates by forming an acyl enzyme through an active site serine. Class B β-lactamases are metalloenzymes that utilize at least one active-site zinc ion to facilitate β-lactam hydrolysis. One of the most efficient and prevalent mechanisms of resistance to β-lactam antibiotics is the production of β-lactamases in both Gram-negative and Gram-positive bacteria that hydrolyze the drugs before they can reach their target and exert the desired effect. These resistance mechanisms are important, and each bacterium can create a combination of defenses depending on the selective pressures placed on it [1-4]. The intrinsic resistance to β-lactam antibiotics was demonstrated to be mainly due to the presence of a chromosomally-encoded gene (blaC) in M. tuberculosis for a Class A, Ambler β-lactamase (BlaC). The BlaC enzyme has already been validated as one of the leading targets of tuberculosis therapy. This enzyme is extremely active against Volume 7 Issue 1 2018