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The endosymbiotic organismWolbachia is an attractive antifilarial drug target. Here we report on the cloning and expression of anrsmD -like rRNA methyltransferase from theWolbachia endosymbiont ofBrugia malayi , its molecular properties, and assays for specific inhibitors. The gene was found to be expressed in all the major life stages ofB. malayi . The purified enzyme expressed inEscherichia coli was found to be in monomer form in its native state. The activities of the specific inhibitors (heteroaryl compounds) against the enzyme were tested withB. malayi adult and microfilariae for 7 daysin vitro at various concentrations, and NSC-659390 proved to be the most potent compound (50% inhibitory concentration [IC50 ], 0.32 μM), followed by NSC-658343 (IC50 , 4.13 μM) and NSC-657589 (IC50 , 7.5 μM). On intraperitoneal administration at 5 mg/kg of body weight for 7 days to adult jirds into whichB. malayi had been transplanted intraperitoneally, all the compounds killed a significant proportion of the implanted worms. A very similar result was observed in infected mastomys when inhibitors were administered. Docking studies of enzyme and inhibitors and anin vitro tryptophan quenching experiment were also performed to understand the binding mode and affinity. The specific inhibitors of the enzyme showed a higher affinity for the catalytic site of the enzyme than the nonspecific inhibitors and were found to be potent enough to kill the worm (both adults and microfilariae)in vitro as well asin vivo in a matter of days at micromolar concentrations. The findings suggest that these compounds be evaluated against other pathogens possessing a methyltransferase with a DPPY motif and warrant the design and synthesis of more such inhibitors.

antimicrobial agents and chemotherapy

Molecular Characterization of an <i>rsmD</i> -Like rRNA Methyltransferase from the Wolbachia Endosymbiont of Brugia malayi and Antifilarial Activity of Specific Inhibitors of the Enzyme

Molecular Characterization of an rsmD -Like rRNA Methyltransferase from the Wolbachia Endosymbiont of Brugia malayi and Antifilarial Activity of Specific Inhibitors of the Enzyme