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NEJM -- Unorthodox Approach to the Development of a New Antituberculosis Therapy (Extract, first two paragraph, edited)
Unorthodox Approach to the Development of a New Antituberculosis Therapy
Clifton E. Barry, III, Ph.D.
The development of TMC207 represents an important advance in the chemotherapy of tuberculosis. It is perhaps most amazing because of the defiantly unconventional nature of the effort.
At virtually every step, from the original discovery of the diarylquinolines by screening for compounds that would kill Mycobacterium smegmatis, a saprophytic distant relative of M. tuberculosis, through the phase 2 study by Diacon et al. reported in this issue of the Journal (ClinicalTrials.gov number, NCT00449644 [ClinicalTrials.gov] ), this effort flouted conventional wisdom about how to develop new drugs for tuberculosis.
It is also a humbling case study that is worth some reflection.
Those of us in the tuberculosis field turned up our noses at looking for compounds that killed anything less than the real human pathogen, and until recently, the whole notion of screening drugs for their ability to provide activity against whole organisms was somewhat anachronistic.
Surely we have advanced in the decades since streptomycin was isolated by Selman Waksman after he performed such a screen.
Give us a nice, isolated enzyme with a high-resolution x-ray crystallographic structure, and we will use the armamentarium of modern drug discovery to treat the hard-to-treat tuberculosis.
The problem, summed up recently by Payne et al.,2 is that this approach does not work for bacteria.
The truly disturbing fact is that we do not understand why.
We can develop exquisitely potent and selective inhibitors of virtually any target we choose, but these inhibitors rarely translate into anything with activity useful against whole cells.
(...)
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<cite cite="http://content.nejm.org/cgi/content/full/360/23/2466?query=TOC">NEJM -- Unorthodox Approach to the Development of a New Antituberculosis Therapy</cite>
Clifton E. Barry, III, Ph.D.
The development of TMC207 represents an important advance in the chemotherapy of tuberculosis. It is perhaps most amazing because of the defiantly unconventional nature of the effort.
At virtually every step, from the original discovery of the diarylquinolines by screening for compounds that would kill Mycobacterium smegmatis, a saprophytic distant relative of M. tuberculosis, through the phase 2 study by Diacon et al. reported in this issue of the Journal (ClinicalTrials.gov number, NCT00449644 [ClinicalTrials.gov] ), this effort flouted conventional wisdom about how to develop new drugs for tuberculosis.
It is also a humbling case study that is worth some reflection.
Those of us in the tuberculosis field turned up our noses at looking for compounds that killed anything less than the real human pathogen, and until recently, the whole notion of screening drugs for their ability to provide activity against whole organisms was somewhat anachronistic.
Surely we have advanced in the decades since streptomycin was isolated by Selman Waksman after he performed such a screen.
Give us a nice, isolated enzyme with a high-resolution x-ray crystallographic structure, and we will use the armamentarium of modern drug discovery to treat the hard-to-treat tuberculosis.
The problem, summed up recently by Payne et al.,2 is that this approach does not work for bacteria.
The truly disturbing fact is that we do not understand why.
We can develop exquisitely potent and selective inhibitors of virtually any target we choose, but these inhibitors rarely translate into anything with activity useful against whole cells.
(...)
-