Final Report

1. Project objective

The objective of this project is to identify potential hits for the activity against Mycobacterium tuberculosis (Mtb), the causative agent of TB.    

2. Project design

The design of the project involved screening a collection of purified natural products offered by Chugai Pharmaceutical for their ability to inhibit the growth of Mtb. We also conducted a screening based on the inhibitory activity of the two enzymatic reactions of Mtb.

3. Results, lessons learned

Growth inhibition screening for Mtb resulted in one chemical group hit.  Although it was a known fermentation product series, no activity against Mtb was previously reported in the literature.  Additional novel analogues were synthesized and tested against Mtb.  The pharmacokinetics and potential toxicological properties of these analogues were investigated, indicating that some of the analogues could be the leads for novel TB drugs.  On the other hand, no promising compounds were found from screening against two enzymatic targets.  Based on these data, a Hit-to-Lead proposal was submitted to GHIT and was accepted (GHIT-RFP-HTLP-2019-002).  This project has confirmed that natural products can be a potential hit source for novel TB drugs.