Mycobacterial Membranes as Actionable Targets for Lipid-Centric Therapy in Tuberculosis

Abstract

Infectious diseases remain significant health concerns worldwide, and resistance is particularly common in patients with tuberculosis caused by Mycobacterium tuberculosis. The development of anti-infectives with novel modes of action may help overcome resistance. In this regard, membrane-active agents, which modulate membrane components essential for the survival of pathogens, present attractive antimicrobial agents. Key advantages of membrane-active compounds include their ability to target slow-growing or dormant bacteria and their favorable pharmacokinetics. Here, we comprehensively review recent advances in the development of membrane-active chemotypes that target mycobacterial membranes and discuss clinically relevant membrane-active antibacterial agents that have shown promise in counteracting bacterial infections. We discuss the relationship between the membrane properties and the synthetic requirements within the chemical scaffold, as well as the limitations of current membrane-active chemotypes. This review will lay the chemical groundwork for the development of membrane-active antituberculosis agents and will foster the discovery of more effective antitubercular agents.

Tuberculosis Drug Discovery: Challenges and New Horizons

“…, inducing permeabilization and upregulating a stress reporter promoter), compound 55 directly inhibits MmpL3 without affecting the membrane charge or proton gradients . Membrane-targeted antibacterial or antitubercular small molecules have been recently reviewed …”

“…179 Membrane-targeted antibacterial or antitubercular small molecules have been recently reviewed. 180 Another well-known class of MmpL3 inhibitors is indolecarboxamides, including NITD-304 (56) and NITD-349 (57) (Figure 6), which were disclosed by Novartis as preclinical candidates in 2013 and provided to the TB Alliance in the following year. 92, 134 Stec et al reported the new analogue 58 (Figure 6), following optimization of their earlier cyclooctylamide lead.…”

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

“…It is thus not surprising that various inhibitors of specific processes of the cell wall biosynthesis [ 8 , 9 , 10 , 11 ] have long been established as a major group of antitubercular drugs. Moreover, the approaches aiming to directly target and modulate the mycobacterial membranes are currently seen as very promising [ 12 ]. Among the cell envelope layers, perhaps the most important protective role belongs to the wax-like outer membrane [ 7 , 8 , 13 ] that has high strength and extremely low permeability for external molecules (especially the relatively hydrophilic ones, including some antibiotics [ 6 ]).…”

Spotlight on mycobacterial lipid exploitation using nanotechnology for diagnosis, vaccines, and treatments

“… 28 Mycobacterial fatty coats are the preferential target for anti-tuberculous drugs. 61 Most bioactive lipids of M. tuberculosis are not addressable in aqueous milieux for biological interactions to occur, but only through nanotechnology approaches. …”