Novel stilbene scaffolds efficiently target<i>Mycobacterium tuberculosis</i>nucleoid-associated protein, HU

Peraman, Ramalingam; Meka, Geethavani; Chilamakuru, Naresh Babu; Kutagulla, Vinay Kumar; Malla, Saloni; Ashby, Charles R.; Tiwari, Amit K.; Yiragamreddy, Padmanabha Reddy

doi:10.1039/d0nj05947a

Cited by 5 publications

(4 citation statements)

References 41 publications

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“…Given the high MIC for SD1 ( Supplementary Table 4 ), we clearly echo that an alternate to SD1 is absolutely essential to take this target to the next level of promising ones. One promising candidate is the small molecule “3d” developed very recently (Peraman et al, 2021 ). We are also currently screening a library of small molecules for an alternate to SD1 and “3d”.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, several Mtb proteins including nucleoid-associated histone-like proteins (NAPs) are under evaluation as novel therapeutic targets (Pinault et al, 2013 ; Bhowmick et al, 2014 ; Peraman et al, 2021 ). Typically, in bacteria, NAPs are known to orchestrate nucleoid dynamics, operate as global transcription modulators, shield nucleoid under stress conditions, and alter cellular responses to stress (Hołówka and Zakrzewska-Czerwińska, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

“…Given its multiple roles, it is not surprising that it has emerged as a key player in influencing Mtb growth in vitro and in alveolar macrophages (Sassetti et al, 2003 ; Pandey et al, 2014a ). Consequently, it has been explored as a novel therapeutic target (Bhowmick et al, 2014 ; Peraman et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics

et al. 2022

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To survive and establish its niche, Mycobacterium tuberculosis (Mtb) engages in a steady battle against an array of host defenses and a barrage of antibiotics. Here, we demonstrate that Mtb employs HupB, a nucleoid-associated protein (NAP) as its key player to simultaneously battle and survive in these two stress-inducing fronts. Typically, NAPs are key to bacterial survival under a wide array of environmental or host-mediated stresses. Here, we report that for Mtb to survive under different macrophage-induced assaults including acidic pH, nutrient depletion, oxidative and nitrosative stresses, HupB presence is critical. As expected, the hupB knockout mutant is highly sensitive to these host-mediated stresses. Furthermore, Mtb aptly modulates HupB protein levels to overcome these stresses. We also report that HupB aids Mtb to gain tolerance to high levels of rifampicin (RIF) and isoniazid (INH) exposure. Loss of hupB makes Mtb highly susceptible to even short exposures to reduced amounts of RIF and INH. Overexpressing hupB in Mtb or complementing hupB in the hupB knockout mutant triggers enhanced survival of Mtb under these stresses. We also find that upon loss of hupB, Mtb significantly enhances the permeability of its cell wall by modulating the levels of several surface lipids including phthiocerol dimycocerosates (PDIMs), thus possibly influencing overall susceptibility to host-mediated stresses. Loss of hupB also downregulates efflux pump expression possibly influencing increased susceptibility to INH and RIF. Finally, we find that therapeutic targeting of HupB with SD1, a known small molecule inhibitor, significantly enhances Mtb susceptibility to INH and THP-1 macrophages and significantly reduces MIC to INH. Thus, our data strongly indicate that HupB is a highly promising therapeutic target especially for potential combinatorial shortened therapy with reduced INH and RIF doses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics

et al. 2022

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Nitschke,

Huber,

Vossio

et al. 2024

Preprint

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This study evaluated the efficacy of a high-throughputDictyostelium discoideum–Mycobacterium marinumDd-Mm infection system by first benchmarking it against a set of antibiotics and second in screening a library of natural product (NP) derivatives for anti-infective activity against intracellularMycobacterium marinum(Mm). The study observed no activity of pyrazinamide against Mm, consistent with known resistance patterns, and confirmed other antibiotics, such as rifampicin and bedaquiline, with activity below defined antibacterial susceptibility breakpoints. From screening a small library of NP derivatives,trans-δ-viniferins emerged as promising anti-infective scaffolds, particularly two compounds which exhibited an anti-infective activity on Mm during infection but not on Mm in broth, with an IC50 of 18.1 µ with an IC50 of 9 µM). Subsequent exploration via halogenation and structure-activity relationship (SAR) studies led to the identification of derivatives with improved selectivity and potency. The observed anti-infective phenotype may involve mechanisms such as blocking mycobacterial virulence factors or boosting host defense. Furthermore, the study highlights the potential of natural product-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.

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Stealing survival: Iron acquisition strategies of Mycobacterium tuberculosis

Shankar,

Akhter

2024

Biochimie

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Novel stilbene scaffolds efficiently targetMycobacterium tuberculosisnucleoid-associated protein, HU

Abstract: A novel scaffolds of stilbene were identified as inhibitors of Mycobacterium tuberculosis by targeting the nucleoid-associated protein, HU, using molecular docking. Based on the proposed combinatorial library I to VI,...

Cited by 5 publications

References 41 publications

HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics

HupB, a nucleoid-associated protein, is critical for survival of Mycobacterium tuberculosis under host-mediated stresses and for enhanced tolerance to key first-line antibiotics

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

Stealing survival: Iron acquisition strategies of Mycobacterium tuberculosis

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