Abstract:
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the
leading causes of death from a single infectious agent worldwide. The high prevalence of this
disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs,
exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the
urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to
those currently being used. An N-alkyl quinolone; decoquinate derivative RMB041, has recently
shown promising antimicrobial activity against Mtb, while also exhibiting low cytotoxicity and
excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown.
Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze
and compare the metabolic alterations of Mtb treated with decoquinate derivative RMB041 by
comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb treated
with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the
urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell
wall and secondarily on the DNA metabolism of Mtb. Additionally, we identified metabolic changes
suggesting inhibition of protein synthesis and a state of dormancy.
