Biochemical Characterization of Isoniazid-resistant Mycobacterium tuberculosis: Can the Analysis of Clonal Strains Reveal Novel Targetable Pathways?

Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates

“…These include drug resistance, metal ion homeostasis ( corA ( Park et al, 2019 ), lpqS ( Darwin, 2015 ), mmpS4 ( Jones et al, 2014 ) , higA ( Schuessler et al, 2013 ) , mbtJ ( Chownk et al, 2018 ), and hemN McMahon et al, 2012 ), and the induction and maintenance of dormancy—all functions with examples of modulation by DNA adenine methylation in other human pathogens (Beaulaurier et al; Brunet et al, 2020 ; Cohen et al, 2016 ; Sánchez-Romero and Casadesús, 2020 ). The resistance-implicating genes among these mediate resistance through gene regulation ( whiB7 -controlled expression of eis, tap, and Rv1473 ( Duan et al, 2019 ; Morris et al, 2005 ), and raaS- controlled expression of Rv1218c and Rv1217c Wang et al, 2013 ), drug efflux ( drrA ( Mustyala et al, 2016 ) , iniA ( Colangeli et al, 2005 ), Rv3728 ( Gupta et al, 2010 ), and efflux-targets of whiB7 and raaS ), and other mechanisms ( glf ( Chen and Bishai, 1998 ) , mshC ( Parida et al, 2015 ) , mshD ( Vilchèze et al, 2008 ) , pafA ( Samanovic and Darwin, 2016 ), Rv3050c ( Nieto R et al, 2018 ), and gyrB ( Nosova et al, 2013 ).…”

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

“…Indeed, a potential link between low PDIM and PGL levels in the M.tb cell envelope with increased drug susceptibility has been reported using a tesA (encoding a type II thioesterase) mutant strain of Mycobacterium marinum ( Chavadi et al, 2011 ). On the other hand, 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, but also with lipid metabolism, virulence, adaptation, and cell envelope remodeling.…”

“…Some evidence indicate that DR- M.tb strains may have a different cell envelope thickness and composition than their counterparts, drug-susceptible strains ( Velayati et al, 2009a , 2010 ; Singh et al, 2015 ; Nieto et al, 2016b , 2018 ). These potential differences in their cell envelope composition and thickness might be further accentuated by host ALF hydrolases and other host innate immune soluble components, differently impacting the interaction of these strains with AMs and subsequent infection progression.…”

Deciphering the mechanism of action of antitubercular compounds with metabolomics

“…is a persistent intracellular pathogen that is intrinsically tolerant to some antibiotics. An untargeted metabolomics approach was successfully used to identify an enzyme that mediates the broad antibiotic tolerance in M. tb [91] , [92] . Metabolic profiling of three different antitubercular drugs, isoniazid, rifampicin, and streptomycin, showed that each targeted different cellular processes but all three triggered the activation of isocitrate lyase (ICL).…”