Turning Mycobacterium tuberculosis appetite for fatty acids against itself

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

Project summary Tuberculosis (TB) remains a leading cause of morbidity and mortality worldwide. In 2020, it is estimated that 1.5 million people died from TB. This calls for improved treatment regimens, which will greatly benefit from the identification of novel strategies to sterilize infections. The overarching idea of this line of research is to subvert highly adaptive strategies employed by the etiological agent of TB Mycobacterium tuberculosis (Mtb). There is a large body of work in support of Mtb exploiting host fatty acids as a carbon source. However, although important for growth and survival, fatty acids can also be toxic for Mtb. Previous work from our laboratory showed that mutants devoid of malate synthase (glcB), type-2 NADH dehydrogenase (ndh/ ndhA) and EtfD (etfD) render a fatty acid sensitive phenotype associated with attenuation in the mouse model of TB. This showed that it is possible to turn Mtb’s optimized metabolism to oxidize host fatty acids against the bacilli. Beyond these specific cases, there is a gap in knowledge on the genetic determinants necessary for Mtb to avoid fatty acid toxicity. To address this issue, we have performed transposon sequencing (Tn-seq) and compared transposon mutant libraries generated in medium with and without oleic acid (a long-chain fatty acid commonly used in mycobacteria culture media, and likely a carbon source during infection). This screening identified ndh and etfD transposon mutants as being sensitive to oleic acid, which is consistent with our previous findings. In this proposal we will do a “deep dive” on the physiological function of the top hit of our Tn-seq screening. Preliminary data indicates that an interplay between cAMP signaling, fatty acid catabolism and respiration impacts Mtb drug susceptibility and pathogenicity. Understanding how these different cell processes interact will not only lead to a better understanding of the pathogen’s biology, but it will unveil new strategies to sterilize Mtb infections.