Mechanisms of Drug-Induced Tolerance in Mycobacterium tuberculosis

Abstract

SUMMARY Successful treatment of tuberculosis (TB) can be hampered by Mycobacterium tuberculosis populations that are temporarily able to survive antibiotic pressure in the absence of drug resistance-conferring mutations, a phenomenon termed drug tolerance. We summarize findings on M. tuberculosis tolerance published in the past 20 years. Key M. tuberculosis responses to drug pressure are reduced growth rates, metabolic shifting, and the promotion of efflux pump activity. Metabolic shifts upon drug pressure mainly occur in M. tuberculosis’s lipid metabolism and redox homeostasis, with reduced tricarboxylic acid cycle activity in favor of lipid anabolism. Increased lipid anabolism plays a role in cell wall thickening, which reduces sensitivity to most TB drugs. In addition to these general mechanisms, drug-specific mechanisms have been described. Upon isoniazid exposure, M. tuberculosis reprograms several pathways associated with mycolic acid biosynthesis. Upon rifampicin exposure, M. tuberculosis upregulates the expression of its drug target rpoB. Upon bedaquiline exposure, ATP synthesis is stimulated, and the transcription factors Rv0324 and Rv0880 are activated. A better understanding of M. tuberculosis’s responses to drug pressure will be important for the development of novel agents that prevent the development of drug tolerance following treatment initiation. Such agents could then contribute to novel TB treatment-shortening strategies.

Screening of Compounds for Anti-tuberculosis Activity, and in vitro and in vivo Evaluation of Potential Candidates

“…In addition, long-term use of these antibiotics has led to the emergence of drug resistance, which poses a huge threat to human life. MDR and XDR Mtb infections have been reported worldwide ( Seung et al, 2015 ; Sander et al, 2020 ). In this study, we found that orbifloxacin had high anti- Mtb bioactivity in vitro with a low MIC of 0.2 μg/ml and protected the mice from infection in vivo .…”

Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?

“…Antibiotics can induce growth and metabolic activity arrest in rapidly growing cells. For example, the antimicrobial effect of INH depends on INH conversion to isonicotinoyl by the catalase-peroxidase katG ( 3 ). Converted isonicotinoyl binds NAD + to make isonicotinoyl-NAD that inhibits mycolic acid synthesis, a bacterial cell wall component, subsequently interfering with mycobacterial cell wall integrity ( 3 ).…”

“…The presence of a mycobacterial population with more than one bacterial phenotype has been observed in patients with TB, as indicated by bacterial populations with varying growth dynamics in sputum samples (3). TB treatment strategy involves long-term treatment with several drugs for at least six months, which may increase the risk of MDR-and XDR-Mtb emergence (4)(5)(6), which is attributed to residual bacteria that are sheltered from or unresponsive to antibiotic treatment in heterogenous mycobacterial populations in patients (3). Thus, enhancing treatment success rate, shortening treatment duration, and preventing MDR Mtb emergence are the most critical factors for successful TB treatment.…”

“…According to the WHO report, in 2020, approximately 10 million people were newly diagnosed, and 1.3 million people died from this notorious disease ( 2 ). Moreover, the recent treatment success rate was 82% for drug-sensitive TB and 55% for multidrug-resistant (MDR)-TB ( 3 ). There has been a gradual increase in the incidence of MDR-TB, defined as resistance to isoniazid (INH) and rifampicin (RIF), and extensively drug-resistant (XDR)-TB, defined as in vitro drug resistance to not only INH and RIF, but also all fluoroquinolones and at least one injectable aminoglycoside ( 4 ).…”

Structural Basis for the C-Terminal Domain of Mycobacterium tuberculosis Ribosome Maturation Factor RimM to Bind Ribosomal Protein S19

“…As a deadly infectious disease, tuberculosis (TB) infected about 10 million people and caused an estimated 1.4 million deaths worldwide in 2019, and the responsible pathogen for TB is Mycobacterium tuberculosis ( Mtb ) [ 1 ]. Globally, TB has developed resistance to traditional anti-TB drugs like isoniazid and rifampicin, an unfortunate complication to TB prevention and treatment [ 2 , 3 ]. Patients infected with multidrug-resistant TB (MDR-TB) require medicines at higher costs and a longer time for treatment, only receiving a treatment success rate of 57% [ 1 ].…”