Bacteria prefer to exist in biofilms that are composed of specialised non-replicating cells encased within an extracellular matrix of biomolecules and demonstrate tolerance towards every class of antibiotic therapy. The cleavage of N-terminal methionine by MetAP is an important event during protein synthesis and maturation, therefore it is an ideal target for designing new inhibitors against bacterial pathogens. Here, we disclose various diketo acids and their bioisosteres as potential bacterial biofilm and MetAP inhibitors. In the biochemical assays against purified MetAPs from Streptococcus pneumoniae (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds 2, 8, 11 and 13 showed about &gt;70% Inhibition of all the MetAPs at 100µM inhibitor concentration. Moreover, compound 27 found selective inhibitor of MtMetAP by 88% while compound 26 showed HsMetAP inhibition by 93% at 100 µM inhibitor concentration. Selective potent inhibitors were also subjected to cell proliferation assay on CHO cells line and were found to be non-toxic. Growth curve studies for lead inhibitors 11 and 13 indicated their bacteriostatic nature. Significant inhibition of biofilm formation was observed in treated bacterial cells exposed to sub MIC concentrations of inhibitor 13 by Scanning Electron Microscopy (SEM). Transmission Scanning Electron Microscopy (TEM) analysis of bacterial cells exposed to 13 clearly showed morphological changes and intracellular damage as its possible mode of action. Further computational docking studies were performed to investigate the mode of interaction of the most active compounds with the MetAPs active site. The lead inhibitor 13 did not cause an alteration in the hemocyte density in Galleria mellonella larvae thereby not stimulating an immune response. In addition, it was non-toxic up to a concentration of 3.0 mg/ml. The results suggested that 13 could be considered as lead inhibitor and a suitable core for further structural optimization for better and safe antibacterial agents.

Diketo acids and their hybrid bioisoster derivatives as bacterial biofilm and Methionine Aminopeptidase (MetAP) inhibitors

253rd National Meeting (2017)

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