Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling.
Mycobacterium tuberculosis synthesizes specific polyketide lipids that interact with the host and are required for virulence. Using a mass spectrometric approach to simultaneously monitor hundreds of lipids, we discovered that the size and abundance of two lipid virulence factors, phthiocerol dimycocerosate (PDIM) and sulfolipid-1 (SL-1), are controlled by the availability of a common precursor, methyl malonyl CoA (MMCoA). Consistent with this view, increased levels of MMCoA led to increased abundance and mass of both PDIM and SL-1. Furthermore, perturbation of MMCoA metabolism attenuated pathogen replication in mice. Importantly, we detected increased PDIM synthesis in bacteria growing within host tissues and in bacteria grown in culture on odd-chain fatty acids. Because M. tuberculosis catabolizes host lipids to grow during infection, we propose that growth of M. tuberculosis on fatty acids in vivo leads to increased flux of MMCoA through lipid biosynthetic pathways, resulting in increased virulence lipid synthesis. Our results suggest that the shift to host lipid catabolism during infection allows for increased virulence lipid anabolism by the bacterium.
Jain
Madhulika
M
Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, CA 94143, USA.
Petzold
Christopher J
CJ
Schelle
Michael W
MW
Leavell
Michael D
MD
Mougous
Joseph D
JD
Bertozzi
Carolyn R
CR
Leary
Julie A
JA
Cox
Jeffery S
JS
D000214:Acyl Coenzyme A / Q000494:pharmacology; D000818:Animals; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000096:biosynthesis / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D011422:Propionates / Q000494:pharmacology; D014376:Tuberculosis / Q000139:chemically induced; D014774:Virulence / Q000187:drug effects
D000214:Acyl Coenzyme A; D005227:Fatty Acids; D008055:Lipids; D011422:Propionates; C015518:sulfolipids; C015357:methylmalonyl-coenzyme A; C032992:mycocerosic acid; C008901:phthiocerol dimycocerosate; C029658:propionic acid