Diphenyl Urea Compounds Inhibit Growth of Tuberculosis Bacteria

Using advanced genetic engineering techniques to produce enzymes from tuberculosis-causing Mycobacterium in Escherichia coli, researchers have identified a series of chemical compounds that inhibit the recombinant form of an essential enzyme.

Investigators at the University of Birmingham (United Kingdom) used plasmid technology to transfer the three Mycobacterium genes that code for the enzyme inosine monophosphate dehydrogenase (IMPDH) into cultures of E. coli. They found that of the three enzyme isoforms only one, Mt-Guab2, was active in M. tuberculosis at an optimum pH of 8.5 and temperature of 37 °C. The investigators then used recombinant Mt-Guab2 to screen for potential inhibitory drugs.

The Investigators reported in the November 16, 2010, online edition of the journal Microbiology that from a group of 16 diphenyl urea (DPU) compounds, 3 were found to inhibit IMPDH. When tested against living Mycobacterium, these compounds prevented growth of both M. tuberculosis and M. smegmatis. When a plasmid overexpressing the Mt-Guab2 gene was implanted into M. smegmatis, 16 times the amount of DPU was required to inhibit growth.

"IMPDH is essential for cells to proliferate rapidly, which is one of the characteristics of microbial infection as well as human cancers. IMPDH has been used as a target in some anticancer drugs, as blocking the enzyme can prevent proliferation of the cell and induce cell death. Our findings show that inhibiting the bacterial version of IMPDH is a strategy that could be exploited for anti-TB drugs," said senior author Dr. Gurdyal Besra, professor of physiology and chemistry at the University of Birmingham. "The DPU compounds we tested have selective activity against Mycobacterium species, meaning that any future drugs based on these would be specific and would not affect human cells.”

"In the face of growing resistance to current therapies, we desperately need new treatments for TB that are safe and effective,” said Dr. Besra. "We are tapping the potential of a so far unexploited target which could lead to the synthesis of a novel antitubercular drug and our findings, so far are extremely encouraging.”

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