Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment

Abstract

In the last two decades, multi (MDR), extensively (XDR), extremely (XXDR) and total (TDR) drug-resistant Mycobacterium tuberculosis (M.tb) strains have emerged as a threat to public health worldwide, stressing the need to develop new tuberculosis (TB) prevention and treatment strategies. It is estimated that in the next 35 years, drug-resistant TB will kill around 75 million people and cost the global economy $16.7 trillion. Indeed, the COVID-19 pandemic alone may contribute with the development of 6.3 million new TB cases due to lack of resources and enforced confinement in TB endemic areas. Evolution of drug-resistant M.tb depends on numerous factors, such as bacterial fitness, strain’s genetic background and its capacity to adapt to the surrounding environment, as well as host-specific and environmental factors. Whole-genome transcriptomics and genome-wide association studies in recent years have shed some insights into the complexity of M.tb drug resistance and have provided a better understanding of its underlying molecular mechanisms. In this review, we will discuss M.tb phenotypic and genotypic changes driving resistance, including changes in cell envelope components, as well as recently described intrinsic and extrinsic factors promoting resistance emergence and transmission. We will further explore how drug-resistant M.tb adapts differently than drug-susceptible strains to the lung environment at the cellular level, modulating M.tb–host interactions and disease outcome, and novel next generation sequencing (NGS) strategies to study drug-resistant TB.

Host- and age-dependent transcriptional changes in Mycobacterium tuberculosis cell envelope biosynthesis genes after exposure to human alveolar lining fluid

“…Further studies are needed to provide better insight to why E-ALF-exposed M.tb replicates faster than A-ALF-exposed M.tb in both professional and non-professional phagocytes, and to explain why E-ALF status in old age enhances M.tb infection in vitro and in vivo [22, 24, 25] and contributes to elders being more susceptible to respiratory infections in general. Finally, it is important to consider that the cell envelope composition of M.tb is strain-specific, with differences observed in M.tb strains from different lineages, and thus, different ALF-driven alterations in M.tb metabolism may drive different infection progression [77].…”

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

“…This highlights the need for new prevention and treatment strategies for pathogenic bacteria, finding alternatives to antibiotics. The new sequencing technologies are being used to reach such a goal [145]. In this scenario, highly conserved DNA methyltransferases (MTases) are potential targets for epigenetic inhibitors to fight infections [139].…”

In Silico Identification of Possible Inhibitors for Protein Kinase B (PknB) of Mycobacterium tuberculosis

“…Between them, is the ATP pocket. As with most STPKs, it has five main groups that are indispensable for the catalytic process: helix C (residues 51-65); the P-loop (the phosphate-binding or glycine-rich loop) where the amides of the glycines coordinate the phosphates of ATP, functioning as a clamp (residues [18][19][20][21][22][23]; the magnesium positioning loop (residues 156-158); the catalytic loop (residues 135-143); and the activation loop (residues 164-177) (Figure 1). PknB can be found in two conformations, open and closed, depending on the position of the helix C and the P-loop region.…”

“…The usage of these computational tools in the early stages of drug design minimizes failures in later stages and makes the entire process more cost-efficient [21][22][23]. There are multiple published works in which the usage of these tools has led to the discovery of multiple promising compounds against PknB [24][25][26][27][28].…”