InhibitingMycobacterium tuberculosiswithin and without

Abstract

Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials. Attempts to find new lead compounds employing target-based screens were unsuccessful as the leads were inactive against M. tuberculosis Greater success was achieved using phenotypic screening against live tubercle bacilli and this gave rise to the drugs bedaquiline, pretomanid and delamanid, currently in phase III trials. Subsequent phenotypic screens also uncovered new leads and targets but several of these targets proved to be promiscuous and inhibited by a variety of seemingly unrelated pharmacophores. This setback sparked an interest in alternative screening approaches that mimic the disease state more accurately. Foremost among these were cell-based screens, often involving macrophages, as these should reflect the bacterium's niche in the host more faithfully. A major advantage of this approach is its ability to uncover functions that are central to infection but not necessarily required for growth in vitro For instance, inhibition of virulence functions mediated by the ESX-1 secretion system severely attenuates intracellular M. tuberculosis, preventing intercellular spread and ultimately limiting tissue damage. Cell-based screens have highlighted the druggability of energy production via the electron transport chain and cholesterol metabolism. Here, I review the scientific progress and the pipeline, but warn against over-optimism due to the lack of industrial commitment for tuberculosis drug development and other socio-economic factors.This article is part of the themed issue 'The new bacteriology'.

Heterogeneity in tuberculosis

“…It is thought that the prolonged duration of TB treatment is dictated by the fact that at any given time some bacteria are functionally tolerant to the administered drugs, and this is fundamentally a result of granuloma heterogeneity. The search for antibiotics that are active against bacteria across a range of granuloma environments has led to the identification of new classes of antibiotics such as the nitroimidazoles 113–115 and may explain the clinical potency of drugs that target energy metabolism such as bedaquiline 116,117 .…”

Biochemical Investigation of Rv3404c from Mycobacterium tuberculosis

“…2 Treatment for tuberculosis typically requires extensive use of isoniazid, rifampicin, ethambutol, and pyrazinamide for two months followed by an additional four months of isoniazid and rifampicin. 3 Of particular concern is the appearance of multi-drug resistant and extensively drug-resistant bacterial strains, referred to as MDR-TB and XDR-TB, respectively. 4 Treatment is also complicated by the fact those infected with M. tuberculosis may be asymptomatic.…”

The structure of glucose‐1‐phosphate thymidylyltransferase from Mycobacterium tuberculosis reveals the location of an essential magnesium ion in the RmlA‐type enzymes

“…The high‐resolution models presented herein thus provide new and important data for the subsequent design of novel therapeutic inhibitors. Treatment for tuberculosis typically requires extensive use of isoniazid, rifampicin, ethambutol, and pyrazinamide for two months followed by an additional four months of isoniazid and rifampicin . Without the development of shorter and more effective treatments, tuberculosis will remain a worldwide disease responsible for both significant illness and economic devastation.…”