Research Summary
Antibiotics have failed to control bacterial diseases typically due to the emergence of drug resistant (DR) mutants.
Mycobacterium tuberculosis (Mtb) is one of the world’s most successful pathogens because of its capacity to
develop DR mutants to withstand antibiotic effects. Treating DR-tuberculosis (TB) patients takes two years and
costs nearly $393,000 per person, which is substantially more expensive than ~ $49,000 per person for treating
a drug sensitive (DS)-TB patient. Despite this pressing human health problem, little is known about the
mechanistic bases underlying the development of DR-TB. Given the low genomic mutation rates and slow
replication of Mtb, intrinsic bacterial factors should play an important role in developing DR-TB, but they have
been understudied. Accumulating evidence has shown that cyclic formation of Mtb persisters, a phenotypic
variant transiently tolerant to TB antibiotics, can predispose TB patients to the emergence of permanent DR
mutants. We recently reported untargeted metabolomics profiling of Mtb persisters and revealed that Mtb shifted
its trehalose-mediated carbon flux towards the biosynthesis of central carbon metabolism (CCM) intermediates
to avoid irreversible antibiotic damage, while decreasing its flux towards the biosynthesis of cell wall mycolyl
glycolipids. This process was termed the “trehalose catalytic shift” and was identified to be essential for Mtb
persister formation, viability, and drug tolerance. In this application, we hypothesize that the trehalose catalytic
shift is an adaptive strategy executed by Mtb after treatment with TB antibiotics to achieve drug tolerance and
also to facilitate the development of DR mutants, thus altering the TB disease course. In cross-sectional studies
with 7 different clinical TB lineages, lineage 2 strains such as HN878 W-Beijing strain (HN878), have been
associated with a high risk of developing multidrug resistant (MDR)-TB and high mortality. Thus, we will examine
our hypothesis by demonstrating that HN878 is hypervirulent and more prone to develop drug resistance than
other lineage strains because of its high level of trehalose catalytic shift activity. To this end, we will determine if
the trehalose catalytic shift is an HN878 intrinsic factor responsible for its drug tolerance, DR mutation rates, and
hypervirulence in vitro, ex vivo and then apply it in vivo using a TB murine model. A successful outcome of this
application will aid in the development of new therapeutic interventions to cure DR-TB patients, including those
infected with HN878.