Drug resistant Mycobacterium tuberculosis strains have altered cell envelope hydrophobicity that influences infection outcomes in human macrophages

In recent decades, drug resistant (DR) strains of Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), have emerged that threaten public health. Although M.tb's complex and protective cell envelope has been widely studied, little is known about how levels of peripheral lipids change in relation to drug resistance. In this study, we examined levels of cell envelope lipids [phthiocerol dimycocerosates (PDIMs)], glycolipids [phosphatidyl-myo-inositol mannosides (PIMs)], and PIMs associated lipoglycans [lipomannan (LM); mannose-capped lipoarabinomannan (ManLAM)] of 22 M.tb strains that ranged in drug resistance profile. We show that the PDIMs:PIMs ratio increases as drug resistance increases, and provide evidence of PDIM isomers only present in the DR-M.tb strains studied. Overall, the LM and ManLAM levels did not differ between drug resistance categories, but ManLAM surface exposure increased with drug resistance. Infection of human macrophages revealed that DR-M.tb strains have decreased association compared to drug susceptible (DS) strains, and that the pre-XDR M.tb strain with the largest PDIMs:PIMs ratio had decreased uptake, but increased intracellular growth at early during infection compared to the DS-M.tb strain H₃₇R_v. These findings suggest that PDIMs may play an important role in drug resistance and that an increase in hydrophobic cell envelope lipids may influence M.tb-host interactions.