Mycobacterium tuberculosis Adaptation in Response to Isoniazid Treatment in a Multi-Stress System That Mimics the Host Environment

Abstract

Isoniazid (INH) is an antibiotic that is widely used to treat tuberculosis (TB). Adaptation to environmental stress is a survival strategy for Mycobacterium tuberculosis and is associated with antibiotic resistance development. Here, mycobacterial adaptation following INH treatment was studied using a multi-stress system (MS), which mimics host-derived stress. Mtb H37Rv (drug-susceptible), mono-isoniazid resistant (INH-R), mono-rifampicin resistant (RIF-R), and multidrug-resistant (MDR) strains were cultivated in the MS with or without INH. The expression of stress-response genes (hspX, tgs1, icl1, and sigE) and lipoarabinomannan (LAM)-related genes (pimB, mptA, mptC, dprE1, dprE2, and embC), which play important roles in the host–pathogen interaction, were measured using real-time PCR. The different adaptations of the drug-resistant (DR) and drug-susceptible (DS) strains were presented in this work. icl1 and dprE1 were up-regulated in the DR strains in the MS, implying their roles as markers of virulence and potential drug targets. In the presence of INH, hspX, tgs1, and sigE were up-regulated in the INH-R and RIF-R strains, while icl1 and LAM-related genes were up-regulated in the H37Rv strain. This study demonstrates the complexity of mycobacterial adaptation through stress response regulation and LAM expression in response to INH under the MS, which could potentially be applied for TB treatment and monitoring in the future.

Prominent transcriptomic changes in Mycobacterium intracellulare under acidic and oxidative stress

“…Mycobacteria can adapt to stress conditions, including oxidative stress, nutrient starvation, pH change, and temperature, which elucidate its evolutional adaptation by a refined network of molecular mechanisms [ 10 – 13 ]. The production of reactive oxygen species (ROS) and the acidification of phagosomes are the critical mechanisms that macrophages employ to kill internalized pathogens during infections [ 14 – 17 ].…”

“…These cysteine-modified proteins were associated with oxidation–reduction, fatty acid synthesis, cell wall remodeling, and protein repair [ 10 ]. Recently, Yimcharoen et al investigated the transcriptional response of drug susceptible and resistant Mtb strains after isoniazid exposure under stress conditions that mimic the host environment [ 13 ]. The expression of stress-response genes such as hspX , tgs1 , icl1 , and sigE and lipoarabinomannan (LAM) synthesis associated genes including pimB , mptA , mptC , dprE1 , dprE2 , and embC were highly differentiated between the drug-susceptible and resistant strains [ 13 ].…”

“…Recently, Yimcharoen et al investigated the transcriptional response of drug susceptible and resistant Mtb strains after isoniazid exposure under stress conditions that mimic the host environment [ 13 ]. The expression of stress-response genes such as hspX , tgs1 , icl1 , and sigE and lipoarabinomannan (LAM) synthesis associated genes including pimB , mptA , mptC , dprE1 , dprE2 , and embC were highly differentiated between the drug-susceptible and resistant strains [ 13 ]. These findings suggest the role of stress response and LAM synthesis-associated genes may be pivotal for the adaptation and persistence of Mtb within the host.…”