Understanding lipidomic basis of iron limitation induced chemosensitization of drug-resistant Mycobacterium tuberculosis.

Abstract

Under limited micronutrients condition, Mycobacterium tuberculosis (MTB) has to struggle for acquisition of the limited micronutrients available in the host. One such crucial micronutrient that MTB requires for the growth and sustenance is iron. The present study aimed to sequester the iron supply of MTB to control drug resistance in MTB. We found that iron restriction renders hypersensitivity to multidrug-resistant MTB strains against first-line anti-TB drugs. To decipher the effect of iron restriction on possible mechanisms of chemosensitization and altered cellular circuitry governing drug resistance and virulence of MTB, we explored MTB cellular architecture. We could identify non-intact cell envelope, tampered MTB morphology and diminished mycolic acid under iron restricted MDR-MTB cells. Deeper exploration unraveled altered lipidome profile observed through conventional TLC and advanced mass spectrometry-based LC-ESI-MS techniques. Lipidome analysis not only depicted profound alterations of various lipid classes which are crucial for pathogenecity but also exposed leads such as indispensability of iron to sustain metabolic, genotoxic and oxidative stresses. Furthermore, iron deprivation led to inhibited biofilm formation and capacity of MTB to adhere buccal epithelial cells. Lastly, we demonstrated enhanced survival of Mycobacterium-infected Caenorhabditis elegans model under iron limitation. The present study offers evidence and proposes alteration of lipidome profile and affected virulence traits upon iron chelation. Taken together, iron deprivation could be a potential strategy to rescue MDR and enhance the effectiveness of existing anti-TB drugs.