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Bioconjug Chem. 2013 Mar 20;24(3):443-7. doi: 10.1021/bc3005667. Epub 2013 Mar 1.

Reactive rifampicin derivative able to damage transcription complex.

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PHRI Center and New Jersey Medical School, Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, 225 Warren Street, Newark, NJ 07103, USA.


Rifampicin (Rif) is powerful broad spectrum antibiotic that targets bacterial RNA polymerase (RNAP) by blocking the transcript exit channel. The performance of the drug can be further enhanced by tagging with active chemical groups that produce collateral damage. We explored this principle by tethering Rif to Fe(2+)-EDTA chelate. Modified drug retained high binding affinity to RNAP and caused localized cleavage of the enzyme and promoter DNA. Analysis of the degradation products revealed the cleavage of RNAP β subunit at the sites involved in the drug binding, while DNA was selectively seized in the vicinity of the transcription start site. The synthesized Rif derivative exemplifies "aggressive" types of drugs that can be especially useful for TB treatment by attacking the nongrowing dormant form of the mycobacterium, which is hardly susceptible to "passive" drugs.

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