Key Accomplishments

Our key accomplishments

During the TBSGC program, we have achieved significant insights into the structural biology of Mtb. Further, we have leveraged these insights to probe the physiology of Mtb, with a focus on targets relevant to drug discovery that have led to new projects and collaborations.

We have successfully published 49 primary research publications during the current funded period, including multiple papers in prestigious journals such as Science, Cell, and Nature. Overall, we have contributed over 500 structures to PDB, which have been instrumental in initiating several lead identification and optimization projects with pharmaceutical partners, based on our findings and target inhibitor structures.

Over the past few years, we have developed, refined, and validated a pool of approximately 1400 individually generated inducible hypomorphic mutants of Mtb. This advancement has facilitated high-throughput chemical-genetic interaction (CG) screening both in vitro and in animal models.

We introduced ORBIT, a groundbreaking method that utilizes multiple phage recombinases to enable swift and selectable engineering of insertions and deletions in Mtb. Additionally, we optimized the process of introducing single nucleotide variants into the Mtb genome by circumventing the mycobacterial mismatch repair system. Furthermore, our chemical-genetic screening revealed unforeseen interactions between genes and existing antibiotics, potentially catalyzing the development of more efficacious drugs

High-resolution Cryo-EM studies of the ribosome have yielded valuable insights into ABC-F protein binding and its significant impact on translation processes. Furthermore, by analyzing ribosome structures, we unveiled the molecular mechanisms underlying Mtb’s inherent resistance to macrolide antibiotics, particularly through comparisons with sequanamycins bound to the macrolide binding pocket. These structural findings have also facilitated the development of potent sequanamycin inhibitors capable of overcoming this intrinsic resistance.

Among the entire list of structures solved by the group, few are highlighted below.

View all structures