Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance

Gu, Xinjie; Pisoni, Lily A.; Wang, Yinhu; Song, Di; Sykes, Matthew J.; Qin, Yinhui; Semple, Susan J.; Polyak, Steven W.; Venter, Henrietta; Ma, Shutao

doi:10.1016/j.bioorg.2020.104394

Cited by 7 publications

(14 citation statements)

References 41 publications

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“…The Plant Biochemistry Laboratory hosts a state-of-the-art metabolomics platform. Structural analysis of isolated intermediates using NMR spectroscopy is being carried out with Dan Staerk (Gericke et al, 2020;Kjaerulff et al, 2020;Pedersen et al, 2020;Bredahl et al, 2022) (Ndi et al, 2007;Mon et al, 2015;Biva et al, 2016;Gu et al, 2020). Susan Semple has also pioneered the establishment of collaborative partnerships in projects driven by Australian Aboriginal communities themselves (Claudie et al, 2012).…”

Section: Natural Sciencementioning

confidence: 99%

“…A major challenge in this part of the project was engineering the diterpenoid pathways into a production host. In other research projects, we have been highly successful in elucidating the full pathways for structurally complex transoid-diterpenoids by first producing the linear C20 isoprene precursor and core structures in yeast, and then identifying the P450s involved in the oxygenation of the core structures by the co-expression of putative P450encoding candidate genes and characterizing their functionality by metabolite profiling (Andersen-Ranberg et al, 2016;Pateraki et al, 2017;G€ ulck et al, 2020;Forman et al, 2022;Hansen et al, 2022). In the case of the Eremophila diterpene synthases, their use of the cisoid precursor became a major stumbling block.…”

Section: Natural Sciencementioning

confidence: 99%

See 1 more Smart Citation

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas

Semple

Buirchell²,

Fowler

et al. 2022

The Plant Journal

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SUMMARY In a cross‐continental research initiative, including researchers working in Australia and Denmark, and based on joint external funding by a 3‐year grant from the Novo Nordisk Foundation, we have used DNA sequencing, extensive chemical profiling and molecular networking analyses across the entire Eremophila genus to provide new knowledge on the presence of natural products and their bioactivities using polypharmocological screens. Sesquiterpenoids, diterpenoids and dimers of branched‐chain fatty acids with previously unknown chemical structures were identified. The collection of plant material from the Eremophila genus was carried out according to a ‘bioprospecting agreement’ with the Government of Western Australia. We recognize that several Eremophila species hold immense cultural significance to Australia's First Peoples. In spite of our best intentions to ensure that new knowledge gained about the genus Eremophila and any potential future benefits are shared in an equitable manner, in accordance with the Nagoya Protocol, we encounter serious dilemmas and potential conflicts in making benefit sharing with Australia's First Peoples a reality.

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Section: Natural Sciencementioning

confidence: 99%

Section: Natural Sciencementioning

confidence: 99%

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas

Semple

Buirchell²,

Fowler

et al. 2022

The Plant Journal

Self Cite

View full text Add to dashboard Cite

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“…Scientists have devoted considerable efforts to develop new antibiotics, especially those with novel mechanism of actions and chemical scaffolds important to reduce the emergence of antimicrobial resistance 8–15 . However, discovering novel and effective antibiotics presents a tremendous challenge for medicinal scientists 16–19 .…”

Section: Introductionmentioning

confidence: 99%

“…10 -teixobactin, Fmoc-Arg (Pbf)-OH was first attached to the 2-CTC resin and amino acid residues 9 to 1 were then introduced by standard Fmoc based SPPS.Although the side-chain hydroxyl group of D-Thr 8 was not protected, the O-acylation side reaction was not detected. Then Fmoc-Ile-OH was introduced to construct ester bonds with side-chain hydroxyl group of D-Thr 8 .…”

mentioning

confidence: 99%

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

Tang

Wang

et al. 2022

Journal of Peptide Science

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Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever‐increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide‐based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram‐positive pathogens and Mycobacterium tuberculosis, including drug‐resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l‐allo‐End, natural teixobactin, representative teixobactin analogs, as well as the structure–activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

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“…Our group has had previous success in the use of combined structure-and ligand-based methods for improved understanding of the activity of new inhibitors of AcrAB-TolC in E. coli. 49 The current work aims to further develop and extend this approach to a screening method for a repurposing study. In this study, we have developed an in silico model for predicting compounds which bind strongly to AcrB and therefore are likely to inhibit AcrAB-TolC in E. coli.…”

mentioning

confidence: 99%

Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli

Pisoni,

Semple,

Liu

et al. 2023

ACS Infect. Dis.

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The inhibition of efflux pumps is a promising approach to combating multidrug-resistant bacteria. We have developed a combined structure- and ligand-based model, using OpenEye software, for the identification of inhibitors of AcrB, the inner membrane protein component of the AcrAB-TolC efflux pump in Escherichia coli. From a database of 1391 FDA-approved drugs, 23 compounds were selected to test for efflux inhibition in E. coli. Seven compounds, including ivacaftor (25), butenafine (19), naftifine (27), pimozide (30), thioridazine (35), trifluoperazine (37), and meloxicam (26), enhanced the activity of at least one antimicrobial substrate and inhibited the efflux pump-mediated removal of the substrate Nile Red from cells. Ivacaftor (25) inhibited efflux dose dependently, had no effect on an E. coli strain with genomic deletion of the gene encoding AcrB, and did not damage the bacterial outer membrane. In the presence of a sub-minimum inhibitory concentration (MIC) of the outer membrane permeabilizer colistin, ivacaftor at 1 μg/mL reduced the MICs of erythromycin and minocycline by 4- to 8-fold. The identification of seven potential AcrB inhibitors shows the merits of a combined structure- and ligand-based approach to virtual screening.

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Design and synthesis of novel 4-substituted quinazoline-2-carboxamide derivatives targeting AcrB to reverse the bacterial multidrug resistance

Cited by 7 publications

References 41 publications

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas

Biodiscoveries within the Australian plant genus Eremophila based on international and interdisciplinary collaboration: results and perspectives on outstanding ethical dilemmas

Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance

Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in Escherichia coli

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