Prototype Drug Blocks Critical Tuberculosis Virulence Factor

A chemical compound has been identified that inhibits the activity of the Mycobacterium tuberculosis protein, tyrosine phosphatase mPTPB, and may be the prototype for a new generation of drugs for the treatment of tuberculosis.

The protein tyrosine phosphatase mPTPB from M. tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there has been considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique anti-tuberculosis agents.

In the current study, investigators from the Indiana University School of Medicine (Indianapolis, USA) discovered that mPTPB subverted the host's innate immune responses by blocking the ERK (extracellular signal-regulated kinases)1/2 and p38 mediated production of interleukin-6 (IL-6) and promoted host cell survival by activating the Akt pathway. They reported in the February 18, 2010, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that they had identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity. This compound was subsequently isolated from a combinatorial library of bidentate benzofuran salicylic acid derivatives.

Inhibition of mPTPB with I-A09 in macrophages reversed the altered host immune responses induced by the bacterial phosphatase and prevented growth of M. tuberculosis in host cells.

"The compound synthesized by the Indiana University group is a proof of concept that a small molecule drug targeted against an essential virulent factor of the tuberculosis bacterium can be an effective strategy,” said senior author Dr. Zhong-Yin Zhang, professor of biochemistry and molecular biology at the Indiana University School of Medicine. "If it can be developed into an approved drug, the result could significantly shorten treatment times for tuberculosis.”

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Indiana University School of Medicine