Targeting the trehalose utilization pathways ofMycobacterium tuberculosis

Abstract

Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets.

The trehalose-specific transporter LpqY-SugABC is required for antimicrobial and anti-biofilm activity of trehalose analogues in Mycobacterium smegmatis

“…As discussed recently, trehalose metabolism has received increasing attention as a target for the development of novel anti-tubercular agents. [3,4] Trehalose ( 1 ), a non-mammalian disaccharide, is essential for mycobacterial viability and virulence. Trehalose is responsible for the transport of mycolic acids—long-chain (C 60 –C 90 ), α-branched, β-hydroxy fatty acids—to the exterior of the cell, where they are used to construct the thick, hydrophobic mycobacterial outer membrane, or “mycomembrane.”[5] As shown in Figure 1, cytoplasmic trehalose is converted to trehalose monomycolate (TMM),[6] which is then transported across the plasma membrane by MmpL3.…”

“…Various strategies have been used to develop inhibitors targeting trehalose metabolism, including the rational design of trehalose-based inhibitors. [3] The first example of a trehalose-based inhibitor was reported by Belisle and co-workers, who observed that 6-azido-6-deoxy-α,α′-trehalose (6-TreAz, 8 ) inhibited growth of M. aurum on solid medium (MIC 200 μg/mL). [10] Treatment of M. aurum with a sub-inhibitory concentration of 6-TreAz led to marked reductions in TMM, TDM, and AGM, suggesting that the compound indeed acted on trehalose-mediated mycolic acid export.…”

Tailoring trehalose for biomedical and biotechnological applications

“…Much of the recent progress in this area was covered in a 2016 review by Thanna and Sucheck. 116 Other prokaryotic pathogens also have trehalose metabolic pathways involved in physiology and pathogenesis. 8,9 The importance of trehalose metabolism to insects 3 may provide opportunities for the development of new insecticides.…”

“…Indeed, HTS-based searches for anti-mycobacterial compounds have yielded numerous drug-like small molecules that act on trehalose metabolism, some of which are presently being pursued as possible treatments for tuberculosis. 116 Another approach that has shown promise is the rational design of inhibitors based on the structure of trehalose or trehalose derivatives. In keeping with the theme of this review, here we discuss the synthesis and evaluation of trehalose-based inhibitors in mycobacteria and other systems.…”

Trehalose efficacy in dry eye syndrome treatment after phacoemulsification

“…Изучаются воз-можности трегалозы в восстановлении функции повреждённых белковых молекул при болезни Альцгеймера и хорее Хантингтона [41]. Фермен-ты патогенных микроорганизмов, отвечающие за синтез трегалозы, становятся мишенями для разработки принципиально новых противогрибко-вых и противотуберкулёзных препаратов [37,42]. Способность трегалозы надёжно защищать кле-точные мембраны от повреждающего воздействия низких температур нашла применение в криокон-сервации ооцитов (ЭКО), трансплантации кле-ток и тканей (гепатоцитов, панкрео цитов) [41].…”