Discovery of Novel Antibacterial and Anti-Tubercular Compounds Using Chemical Genetics and Computational Approach Targeted at Phospholipid Biosynthesis

Bacterial membranes undergo dynamic rearrangements during cell division with lateral heterogeneity in phospholipid distribution. An understanding of the synthesis of the cell membrane can provide a basis for the rational design of new antibacterial compounds which will ultimately be developed towards potential new antibiotics. Mounting evidence is implicating the importance of phospholipid in the viability of mycobacteria. The genetically tractable and related organism, Streptomyces coelicolor represents an ideal model for analogous studies on Mycobacteria tuberculosis for the purpose of designing novel classes of anti-tuberculosis drugs targeting the phospholipid biosynthesis pathways.
Genetic and biochemical studies carried out on phosphatidylserine synthase (Pss) and phosphatidylserine decarboxylase (Psd) demonstrated the essentiality of these membrane proteins in S. coelicolor. Alteration of pss expression affects the overall growth and morphology of S. coelicolor (i.e. hyphal growth, branching, septation and sporulation) therefore verified the potential of these proteins as drug targets. Although, the early stage ―hit identification‖ approach using a modest collection of compounds was unsuccessful, further screening of relevant compounds should continue. Structural modifications should be carried out on some of the initial compounds which were devoid of antibacterial activity in order to address the possible pharmacodynamic issues. Protein X-ray crystallography or saturation transfer difference - nuclear magnetic resonance (STD-NMR) spectroscopy of these proteins should also be considered in the event of further futile attempts.