Elucidating the antimicrobial mechanisms of colistin sulfate on Mycobacterium tuberculosis using metabolomics

Considering the disadvantageous of first line anti-tuberculosis (TB) drugs, including poor patient adherence, drug side effects, the long treatment duration and rapidly increasing microbe resistance, alternative treatment strategies are needed. Colistin sulfate (CS), a polymyxin antibiotic considered a last-resort antibiotics for treating multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter, has antimicrobial activity towards mycobacteria, and could serve as a possible anti-TB drug. Using GCxGC-TOFMS metabolomics, we compared the metabolic profiles of Mycobacterium tuberculosis (Mtb) cultured in the presence and absence of CS, to elucidate the mechanisms by which this drug may exert its antimicrobial effects. The principal component analysis of the metabolite data indicated significant variation in the underlying metabolite profiles of the groups. Those metabolites best explaining this differentiation, were acetic acid, and cell wall associated methylated and unmethylated fatty acids, and their alcohol and alkane derivatives. The elevated glucose levels, and various glyoxylate and glycerolipid metabolic intermediates, indicates an elevated flux in these metabolic pathways. Since all the metabolites identified in the colistin treated Mtb indicates an increase in fatty acid synthesis and cell wall repair, it can be concluded that CS acts by disrupting the cell wall in Mtb, confirming a similar drug action to other organisms.