SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Abstract

Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

Phytochemical, Cytotoxicity, and Antimycobacterial Activity Evaluation of Extracts and Compounds from the Stem Bark of Albizia coriaria Welw ex. Oliver

“…A unique feature of M. tuberculosis ATP synthase is the suppression of the ATP hydrolase activity and its inability to establish a proton gradient. This is thought to be an adaptive mechanism to prevent wastage of ATP during low oxygen conditions [ 40 ]. Bedaquiline, a newly approved antitubercular drug, binds to ATP synthase inhibiting it from releasing energy for the mycobacterial cellular activity resulting in the death of the mycobacterium [ 41 ].…”

The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors

“…Thus, we propose that innovative antimycobacterial strategies disrupting energy metabolism should target both of these two pathways for the best outcome. The latest developments on inhibitors interfering with energy-metabolism in M. tuberculosis are covered in comprehensive reviews ( Thompson and Denny, 2019 ; Appetecchia et al, 2020 ). Not surprisingly, partial depletion of Mtb DarG (Rv0060), the hydrolase antitoxin reversing DarT-catalyzed DNA ADP-ribosylation ( Jankevicius et al, 2016 ), sensitizes the mycobacterial cell to drugs targeting respiration (i.e., bedaquiline) and DNA metabolism ( Zaveri et al, 2020 ).…”

Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

“…The substituted N-benzyl group at the side-chain linked with the secondary carboxamide linker is important for anti-mycobacterial activity but not critical for the activity [94,98,99,101]. The lipophilic chain contains a para-substituted phenyl group that is well tolerated and improved the activity of Q203 [42]. The heterocyclic rings like piperidine and piperazine joining the benzyl group and the para-substituted phenyl group in the lipophilic chain showed an enhanced potency as compared to the heteroaromatic rings [102,103].…”

“…In this context, substituting the naphthalene ring with 3,5-dialkoxy-4-pyridyl in bedaquiline led to two second-generation diarylquinolines, TBAJ-587 and TBAJ-876, both of which had a substantial reduction in lipophilicity [39,40]. In comparison with BDQ, the TBAJ 587 and TBAJ 876 were better in terms of hERG (human ether-à-go-go related gene) channel blockage, with larger IC50 values [39,41,42]. Squaramide derivatives that target the ATP synthase have recently been discovered through high throughput screening and found to be active against bedaquiline resistant strains [43].…”