Diarylethenes Display In Vitro Anti-TB Activity and Are Efficient Hits Targeting the Mycobacterium tuberculosis HU Protein

Abstract

Tuberculosis continues to be a great source of concern in global health because of the large reservoir of humans infected with the bacilli and the appearance of clinical isolates resistant to a wide array of anti-tuberculosis drugs. New drugs with novel mechanisms of action on new targets are urgently required to reduce global tuberculosis burden. Mycobacterium tuberculosis nucleoid associated protein (NAP) HU has been shown to be druggable and essential for the organism’s survival. In this study, four diarylethenes were synthesized using a one-pot decarboxylated Heck-coupling of coumaric acids with iodoanisoles. The prepared compounds 1–4 were tested for their in vitro growth inhibition of M. tuberculosis H37Rv using the spot culture growth inhibition assay, displaying minimum inhibitory concentrations between 9 and 22 µM. Their cytotoxicity against BHK-21 cell line showed half inhibition at concentrations between 98 and 729 µM. The most selective hit (SI = 81), demonstrated inhibition of M. tuberculosis HU protein involved in maintaining bacterial genome architecture.

G-Quadruplex-Forming DNA Aptamers Inhibit the DNA-Binding Function of HupB and Mycobacterium tuberculosis Entry into Host Cells

“… 5 , 40 Utilizing the structural information of NTD, diarylethene derivatives were recently reported that inhibited HupB binding to DNA and blocked the growth of axenic Mtb cultures in vitro . 12 , 13 However, only recently has the importance of HupB CTD in modulating NTD driven DNA processes in vitro and in vivo been reported. 4 , 5 , 40 Moreover, M. smegmatis strains expressing HupB ΔCTD as well as M. smegmatis ΔhupB 10 exhibited higher sensitivity to Isoniazid, compared to wild-type bacteria.…”

“…In conclusion, Mtb HupB has been suggested to be a potent drug target; 3 , 12 , 13 however, the lack of structural knowledge of the full-length protein has impeded the development of potent inhibitors. In the current study, we have overcome this limitation by exploiting SELEX technology, which does not require structural information of the target to develop target specific inhibitors.…”

“… 4 , 9 , 10 Diarylethene derivatives that perturb the DNA-binding function of the HupB-NTD have been characterized recently. 11 , 12 However, inhibitors targeting full-length HupB are expected to be more potent in curtailing bacterial entry, mycobacterial growth, and dissemination, while simultaneously enhancing bacterial sensitivity to Isoniazid. 4 , 11 , 13 Because structural details of HupB available so far are insufficient to pursue the classical drug discovery approach, we adopted the approach of designing and generating target-specific DNA aptamers to bypass this limitation.…”

Role of the DNA-Binding Protein pA104R in ASFV Genome Packaging and as a Novel Target for Vaccine and Drug Development

“…The most promising of the two compounds, SD4 (MtbHU-in-1), showed low cytotoxicity and reduced ASFV replication in a dose dependent manner, which, the authors argue, further confirms the vital role of pA104R in the ASFV replication cycle and highlights its potential as a target for antiviral therapy. Several other compounds from this class have demonstrated antimycobacterial properties [ 109 , 110 , 111 ] but have yet to be tested against ASFV.…”

Discovery of anti-infective compounds againstMycobacterium marinumafter biotransformation of simple natural stilbene scaffolds by a fungal secretome

“…This approach yielded more than 70 compounds distributed in six scaffolds. Since stilbene derivatives have been reported to have potential anti-TB activity in various in vitro assays (Peraman et al, 2021; Reinheimer et al, 2018; Suarez et al, 2017), this library was subjected to an anti-infective screening workflow in the Dd-Mm infection model. The goal of our proof-of-concept study was to develop and benchmark the Dd-Mm system to high-throughput capacity in order to screen a focused library of natural products derivatives for anti-infective and antivirulence activities.…”