Drug discovery teams around the world have been actively selecting targets that are likely to be important in killing dormant or very slowly replicating tuberculosis in an effort to shorten the time to cure; for drug sensitive TB, six to nine months treatment time and drug resistant TB, up to two years treatment time. Some of these targets have been processed through high throughput screening (HTS) campaigns comprising millions of compounds but little to no follow up on the hits from these screening campaigns has been reported. Often when a person discusses these targets with the scientists that performed the HTS, the standard response is that these targets are “non-druggable”.

Whether it’s a lousy target, the compound collection screened was or was not the best fit or there was limited bacterial potency in the follow-up bacterial cell assays remains unclear. In an effort to determine what targets have or have not been processed and why, The Stop TB Working Group for New Drugs Biology/Targets Sub-group is seeking to triage the best drug targets. First, we are attempting to understand what has been done to date by different groups through surveys and direct communication.

Out of frustration or a lack of productive results, many scientists are abandoning target based screens in lead optimization efforts in favor of phenotypic screens using whole cell bacteria. However, this approach leaves medicinal chemists working blind with respect to new directions in lead optimization efforts to drive compound potency, and for M. tuberculosis, the question of cell culture media and carbon sources can derail a drug discovery effort due to altered bacterial physiology. Drug screening campaigns that integrate both physiologically-relevant phenotypic screens and target-based efforts may be the middle path and a faster way to generating new drug leads for tuberculosis.

Would you like to get involved? What targets are you working on? What targets have you worked on? What challenges or hurdles did you come across? Please contact the WGND Biology/Targets subgroup with any information that you believe will aid and speed TB drug discovery.