Multiple routes to tackling drug resistant tuberculosis Systems modeling to unravel resistance mechanisms drug combinations and novel host based biomarkers

Abstract

Tuberculosis (TB), a deadly bacterial infection caused by Mycobacterium tuberculosis (Mtb), has been a major public health problem and the leading cause of death due to infectious disease worldwide. In 2018 about 10 million cases of TB were reported with 1.45 million TB- related deaths. Given its large population, India carries one of the highest burdens of TB and contains a quarter of the world s cases, with 2.69 million cases and about 449,700 deaths. newlineThe successful treatment of TB requires a long-term (minimum of 6-months) multidrug newlinechemotherapy. However, due to poor patient compliance and non-adherence to lengthy newlineanti-TB treatment therapy and drug toxicity, an increased prevalence of drug-resistant newlineTB and subsequent treatment failure have been reported. Several mechanisms facilitate newlinedrug resistance in Mtb. These mechanisms include mutations in the target, expression newlineof enzymes that inactivate or modify the drug compound, overexpression of the target, newlinemodification in the cell wall that affects drug permeability, and increased expression of drug efflux pumps and transporters. However, if one mechanism predominates at a given instance or if multiple mechanisms are responsible for the final resistant phenotype, or if such mechanisms are influenced by each other and lead to global alterations in the cell in a synchronized manner. A systems perspective of underlying drug resistance mechanisms is necessary to rationally select strategies for tackling drug-resistant cases by discovering new newlinetargets and novel drugs. Several other measures are also critical for controlling the spread of drug-resistant TB. For example, detecting a drug-resistant infection early in patients is essential for switching to second-line therapies...