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.
Highlights
Tuberculosis (TB) kills one person every 21s, with ∼10 million cases and ∼1.5 million attributed deaths in 2018 (WHO, 2019)
We find mycobacterial membrane protein Large 3 (MmpL3), Rv3143/Rv1524 axis, and decaprenylphosphoryl-D-ribose 2 -epimerase (DprE), which are involved in the export and synthesis of the M.tb cell wall, regulating its permeability (Dong et al, 2020)
The emergence of drug-resistant TB (DR-TB) may be worsened by the current COVID-19 pandemic, exacerbating the global health crisis and undermining TB prevention and control strategies
Summary
Tuberculosis (TB) kills one person every 21s, with ∼10 million cases and ∼1.5 million attributed deaths in 2018 (WHO, 2019). A recent study used two genetically distinct M.tb clonal pairs (laboratory and clinical drug-sensitive strains and their derived isoniazid-resistant (INHr) mutants) to determine specific in vitro changes related to the isoniazid-resistant phenotype through proteomic and lipidomic analyses (Nieto et al, 2018) These INHr isolates presented 26 proteins with altered levels, which were mainly associated with energy metabolism and respiration, and with lipid metabolism, virulence, adaptation, and cell envelope remodeling. Of the two INHr mutants studied, only the clinical INHr isolate presented low levels of TDM, TMM (trehalose monomycolate) and PDIM, the latter associated with reduced virulence of this strain (Nieto et al, 2016a) This is in contrast with previous studies, indicating that M.tb genetic background may play and important role in determining the remodeling of the M.tb cell envelope protein and lipid constituents after acquisition of drug resistance (Table 1). Unbiased whole transcriptome approach. High-throughput and relatively cost-effective. Higher sensitivity and specificity compared to other gene expression approaches
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