Chemical Tools for Illumination of Tuberculosis Biology, Virulence Mechanisms, and Diagnosis

Abstract

Tuberculosis (TB) remains one of the deadliest infectious diseases and begs the scientific community to up the ante for research and exploration of completely novel therapeutic avenues. Chemical biology-inspired design of tunable chemical tools has aided in clinical diagnosis, facilitated discovery of therapeutics, and begun to enable investigation of virulence mechanisms at the host−pathogen interface of Mycobacterium tuberculosis. This Perspective highlights chemical tools specific to mycobacterial proteins and the cell lipid envelope that have furnished rapid and selective diagnostic strategies and provided unprecedented insights into the function of the mycobacterial proteome and lipidome. We discuss chemical tools that have enabled elucidating otherwise intractable biological processes by leveraging the unique lipid and metabolite repertoire of mycobacterial species. Some of these probes represent exciting starting points with the potential to illuminate poorly understood aspects of mycobacterial pathogenesis, particularly the host membrane−pathogen interactions.

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

“…Understanding lipid organization in the mycobacterial membrane may help guide the design of novel membrane-active antimicrobial drugs. Moreover, as many of the cell envelope lipids exert other important roles that contribute to the pathogenicity of Mtb , they have emerged as promising diagnostic biomarkers and therapeutic targets. , …”

“…Moreover, as many of the cell envelope lipids exert other important roles that contribute to the pathogenicity of Mtb, they have emerged as promising diagnostic biomarkers and therapeutic targets. 71,72 The Mtb membrane envelope is organized into distinct compartments: the plasma or inner membrane, the peptidoglycan (PG)−arabinogalactan (AG) complex, the outer membrane (also referred to as mycomembrane), mycolic acids (MAs) covalently attached to the inner leaflet of the outer membrane, and free lipids noncovalently attached to the outer leaflet of the outer membrane (Figure 2). 73 This arrangement supports the structural, mechanical, metabolic, and osmotic functions of Mtb during different stages of infection.…”

Rediscovery of 4‐Trehalosamine as a Biologically Stable, Mass‐Producible, and Chemically Modifiable Trehalose Analog

“…An increasing number of published studies have reported on the staining of mycobacteria with labeled trehaloses, including 4-fluorescent-and 4-azido-trehaloses. [41][42][43][44][45][46][47] Mycobacteria have a thick cell wall with an outer membrane composed of several major lipids, including trehalose monomycolate (TMM) and trehalose dimycolate (TDM). TMM and TDM are synthesized in mycobacteria in processes involving multiple enzymes, transporters, and trehalose incorporation.…”

“…[48] Trehalose analogs, including fluorescently labeled ones, could be reportedly incorporated into TMM and TDM instead of trehalose. [41][42][43][44][45][46][47] Certain types of mycobacteriosis, such as that caused by multidrug-resistant tuberculosis and nontuberculous mycobacteria, are currently regarded as serious health problems worldwide. [49,50] The labeled trehalose probes could be new helpful tools to detect the pathogens of these mycobacterioses or investigate cell wall structures and functions as well as biosynthesis-related enzymes and transporters to develop new antibiotics and treatments.…”

“…Since the report of Backus et al, [41] several fluorescent trehaloses have been developed to stain mycobacteria. [42][43][44][45][46][47] The currently available good probes are more advantageous for staining living cells than the probes investigated in this study. However, it was demonstrated that the C-4 of trehalose could be modified to create probes for mycobacterial staining, and 4-trehalosamine would be a good material for the development of better probes in the future.…”