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

, the causative agent of tuberculosis (TB), is considered one of the top infectious killers in the world. In recent decades, drug resistant (DR) strains of have emerged that make TB even more difficult to treat and pose a threat to public health. has a complex cell envelope that provides protection to the bacterium from chemotherapeutic agents. Although cell envelope lipids have been studied for decades, very little is known about how their levels change in relation to drug resistance. In this study, we examined changes in the cell envelope lipids [namely, phthiocerol dimycocerosates (PDIMs)], glycolipids [phosphatidyl--inositol mannosides (PIMs)], and the PIM associated lipoglycans [lipomannan (LM); mannose-capped lipoarabinomannan (ManLAM)] of 11 strains that range from drug susceptible (DS) to multi-drug resistant (MDR) to pre-extensively drug resistant (pre-XDR). We show that there was an increase in the PDIMs:PIMs ratio as drug resistance increases, and provide evidence of PDIM species only present in the DR- strains studied. Overall, the LM and ManLAM cell envelope levels did not differ between DS- and DR- strains, but ManLAM surface exposure proportionally increased with drug resistance. Evaluation of host-pathogen interactions revealed that DR- strains have decreased association with human macrophages compared to DS strains. The pre-XDR strain with the largest PDIMs:PIMs ratio had decreased uptake, but increased intracellular growth rate at early time points post-infection when compared to the DS- strain HR. These findings suggest that PDIMs may play an important role in drug resistance and that this observed increase in hydrophobic cell envelope lipids on the DR- strains studied may influence -host interactions.