Covalent inhibitors of bacterial peptidoglycan biosynthesis enzyme MurA with chloroacetamide warhead

Grabrijan, Katarina; Hrast, Martina; Proj, Matic; Dolšak, Ana; Zdovc, Irena; Imre, Tı́mea; Petri, László; Ábrányi‐Balogh, Péter; Keserü, György M.; Gobec, Stanislav

doi:10.1016/j.ejmech.2022.114752

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…A previous study also showed that several chloroacetamide-based MurA covalent inhibitors (47 fragment-sized chloroacetamide scaffolds) were not active against E. coli . 9 In contrast, a less studied warhead, chloromethyl ketone, has the highest hit discovery rate in both V. cholerae and S. aureus screenings.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the rising interest in cysteine targeting compounds, [6][7][8] previous studies primarily used very small libraries with a limited number of cysteine warheads like chloroacetamide. 9,10 The limitation of warhead diversity could hinder the identification of druggable protein targets. The diverse properties and reactivities of bacterial cysteinome may require a broader range of warheads to effectively interact with and modify target proteins.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic screening of covalent compound libraries identifies chloromethyl ketone antibiotics and MiaA as a new target

Jin,

Jana,

Abbasov

et al. 2024

Preprint

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The emerging antibiotic resistance requires the development of new antibiotics working on novel bacterial targets. Here, we reported an antibiotic discovery workflow by combining the cysteine-reactive compound library phenotypic screening with activity-based protein profiling, which enables the rapid identification of lead compounds as well as new druggable targets in pathogens. Compounds featuring chloromethyl ketone scaffolds exhibited a notably high hit rate against both gram-negative and gram-positive bacterial strains, but not the more commonly used warheads such as acrylamide or chloroacetamide. Target identification of the lead compound, 10-F05, revealed that its primary targets in S. flexneri are FabH Cys112 and MiaA Cys273. We validated the target relevance through biochemical and genetic interactions. Mechanistic studies revealed modification of MiaA by 10-F05 impair substrate tRNA binding, leading to decreased bacterial stress resistance and virulence. Our findings underscore chloromethyl ketone as a novel antibacterial warhead in covalent antibiotic design. The study showcases that combining covalent compound library phenotypic screening with chemoproteomics is an efficient way to identify new drug targets as well as lead compounds, with the potential to open new research directions in drug discovery and chemical biology.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenotypic screening of covalent compound libraries identifies chloromethyl ketone antibiotics and MiaA as a new target

Jin,

Jana,

Abbasov

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This pattern was consistent with irreversible inhibition of 13b against E. coli MurA, and therefore, suggestive of either covalent or very tight non-covalent binding. 35–38…”

Section: Resultsmentioning

confidence: 99%

“…This pattern was consistent with irreversible inhibition of 13b against E. coli MurA, and therefore, suggestive of either covalent or very tight non-covalent binding. [35][36][37][38] Structure-activity relationship (SAR) study for inhibitory activity against E. coli MurA and S. aureus Mur A and MurZ enzymes. Some structure-activity trends observed in a series of these 4H-pyrano [2,3-d]pyrimidine-1H-1,2,3-triazoles, in the IC 50 range below 2 mM, were that the electron-donating groups (such as hydroxyl and methoxy groups) as well as the electronwithdrawing (such as nitro and chloro groups) on positions of the benzene ring had similar affects to the inhibitory activity against tested enzymes, in general.…”

Section: Pharmacologymentioning

confidence: 99%