Abstract
Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb). Therapy requires prolonged treatment with a combination of multiple agents and interruptions in the treatment regimen result in emergence and spread of multi-drug resistant (MDR) Mtb strains. MDR Mtb poses a significant global health problem, calling for urgent development of novel drugs to combat TB. Here, we report the 3.3 Å resolution structure of the ~2 MDa type-I fatty acid synthase (FAS-I) from Mtb, determined by single particle cryo-EM. Mtb FAS-I is an essential enzymatic complex that contributes to the virulence of Mtb, and thus a prime target for anti-TB drugs. The structural information for Mtb FAS-I we have obtained enables computer-based drug discovery approaches, and the resolution achieved by cryo-EM is sufficient for elucidating inhibition mechanisms by putative small molecular weight inhibitors.
Highlights
Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb)
Mycolic acids are C74–C90 fatty acids that are synthesized by a unique combination of two canonical enzymatic systems that Mtb has: a fatty acid synthase-II (FAS-II) that is comprised of a group of discrete enzymes, a system that is typically found in plants and prokaryotes
The lack of structural information at near atomic resolution for the Mtb FAS-I system hinders the ability to investigate the mechanism by which PZA or its analogs inhibit FAS-I, and precludes rational design approaches for developing novel inhibitors as potential TB therapeutics
Summary
Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb). Therapy requires prolonged treatment with a combination of multiple agents and interruptions in the treatment regimen result in emergence and spread of multidrug resistant (MDR) Mtb strains. MDR Mtb poses a significant global health problem, calling for urgent development of novel drugs to combat TB. We report the 3.3 Å resolution structure of the ~2 MDa type-I fatty acid synthase (FAS-I) from Mtb, determined by single particle cryo-EM. The structural information for Mtb FAS-I we have obtained enables computer-based drug discovery approaches, and the resolution achieved by cryo-EM is sufficient for elucidating inhibition mechanisms by putative small molecular weight inhibitors. TB is caused by Mycobacterium tuberculosis (Mtb) and for curing TB, a prolonged treatment with a combination of multiple agents is required[1]. Novel drugs that could target MDR Mtb are urgently needed to combat TB. Differences in the catalytic domains of Mtb FAS-I compared to a structurally similar fungal FAS-I homolog suggest a possibility to target Mtb FAS-I with high specificity that would be needed to minimize undesired toxicity toward other systems like the human FAS-I
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
