Drug-resistant strains of Mycobacterium tuberculosis: cell envelope profiles and interactions with the host

Abstract

In the past few decades, drug-resistant (DR) strains of Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), have become increasingly prevalent and pose a threat to worldwide public health. These strains range from multi (MDR) to extensively (XDR) drug-resistant, making them very difficult to treat. Further, the current and future impact of the Coronavirus Disease 2019 (COVID-19) pandemic on the development of DR-TB is still unknown. Although exhaustive studies have been conducted depicting the uniqueness of the M.tb cell envelope, little is known about how its composition changes in relation to drug resistance acquisition. This knowledge is critical to understanding the capacity of DR-M.tb strains to resist anti-TB drugs, and to inform us on the future design of anti-TB drugs to combat these difficult-to-treat strains. In this review, we discuss the complexities of the M.tb cell envelope along with recent studies investigating how M.tb structurally and biochemically changes in relation to drug resistance. Further, we will describe what is currently known about the influence of M.tb drug resistance on infection outcomes, focusing on its impact on fitness, persister-bacteria, and subclinical TB.

Drug resistantMycobacterium tuberculosisstrains have altered cell envelope hydrophobicity that influences infection outcomes in human macrophages

“…Previous studies suggests that PDIMs may be a critical component to protect the impermeability of the M.tb cell envelope, as PDIMs deficiency is linked to increased susceptibility of mycobacteria to anti-TB drugs. 3, 11–13 However, there are very few studies directed at the PDIMs levels in DR- M.tb strains. 15 Here, we performed an exhaustive lipid extraction on three DS-, three MDR-, and five pre-XDR- M.tb strains and analyzed their total lipid extracts using TLC with validation by LC-MS. Our TLC analysis showed that PDIMs levels increase as the drug resistance profile increases, where pre-XDR M.tb strains had the largest increase in PDIMs levels when compared to DS- M.tb strains H 37 R v , Erdman, and CDC1551 ( Fig.…”

“…Previous studies suggest that a deficiency in the hydrophobic cell envelope lipid PDIMs results in increased cell envelope permeability and greater susceptibility of mycobacteria to anti-TB drugs. 3, 11–13 However, there are very few studies indicating increased levels of PDIMs in DR- M.tb strains. 15 Here we biochemically examined the cell envelope lipid composition of 11 M.tb strains that range from DS (including H 37 R v , Erdman, and CDC1551) to MDR and pre-XDR.…”

“…Conversely, phosphatidyl- myo -inositol mannosides (PIMs), especially the higher- order PIMs and their associated lipoglycans [namely, lipomannan (LM) and mannose-capped lipoarabinomannan (ManLAM)], are considered hydrophilic cell envelope molecules. 3, 4 Previous studies examining PIMs, LM, and ManLAM found that they play multiple roles in M.tb -host interactions. 16–22 In relation to drug resistance and virulence, data suggest greater variability in the size and branching of ManLAM in DR- and/or hypervirulent M.tb strains.…”

“…The M.tb cell envelope is a dynamic and protective barrier and a target of various anti-TB drugs. 3 Approximately 80% of the M.tb cell envelope is comprised of carbohydrates and lipids. 4 The inner portion contains a plasma membrane and the covalently link cell wall ‘core’ that is sequentially comprised of peptidoglycan, arabinogalactan (AG) and the mycolic acid layers.…”

Gallein and isoniazid act synergistically to attenuateMycobacterium tuberculosisgrowth in human macrophages

“…61]. Multi-drug resistant Mtb have thicker cell envelopes[62]. INH caused many, but not all, Mtb cells to have thickened cell envelopes.…”