DRUG DISCOVERY OF NEWER ANALOGS OF ANTI-MICROBIALS THROUGH ENZYME-INHIBITION: A REVIEW
Keywords:
L-lysine, Antimicrobial resistance, Diaminopimelic acid, Enzyme inhibitors, Diaminopimelate epimeraseAbstract
There is a growing interest towards the development of new antibiotics from last decades due to emergence of newer pathogenic bacterial strains with high resistance to powerful antibiotics of last resort. This has caused decline in research for developing newer antibacterial agents. Hence, there is continuous need to develop newer antibiotics that interact with essential mechanisms in bacteria. Recently, enzymes responsible for bio synthesis of the essential amino acid lysine in bacteria have been targeted and it has augmented interest to develop novel antibiotics and to enhance lysine yields in over-producing organisms. Peptidoglycan layer consists of a beta-1,4-linked polysaccharide of alternating N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) sugar units, cross linked by short pentapeptide (muramyl residues) side chain of general structure L-Ala-g-D-Glu-X- D-Ala-D-Ala, where X is either L–Lysine or meso-DAP. Formation of the cross-links makes bacterial cell wall resistant to lysis by intracellular osmotic pressure. Compounds which inhibit lysine or DAP biosynthesis could therefore be very effective antibiotics and novel targets. Lysine is a constituent in gram-positive bacteria while meso-DAP occurs in gram negative ones. In this review, substrate-based inhibitors of enzymes in the DAP pathway and inhibitors that allow better understanding of enzymology of the targets and provide insight for design of new inhibitors have been discussed. Resistant bacterial strains can be inhibited by using synthetic enzyme inhibitors of DAP pathway that are less toxic to mammals. Newer antimicrobial drugs can be thus developed by targeting the enzymes involved in this pathway.
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