Structure of Type-I Mycobacterium tuberculosis fatty acid synthase at 3.3 Å resolution.
Nadav EladSzilvia BaronYoav PelegShira AlbeckJacob GrunwaldGal RavivZippora ShakkedOren ZimhonyRon DiskinPublished in: Nature communications (2018)
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.
Keyphrases
- mycobacterium tuberculosis
- pulmonary tuberculosis
- drug resistant
- multidrug resistant
- fatty acid
- drug discovery
- global health
- escherichia coli
- public health
- acinetobacter baumannii
- pseudomonas aeruginosa
- staphylococcus aureus
- emergency department
- hydrogen peroxide
- combination therapy
- machine learning
- healthcare
- bone marrow
- nitric oxide
- biofilm formation
- hepatitis c virus
- replacement therapy
- human immunodeficiency virus