Hit optimization by dynamic combinatorial chemistry on <i>Streptococcus pneumoniae</i> energy-coupling factor transporter ECF-PanT

Exapicheidou, Ioulia Antonia; Shams, Atanaz; Ibrahim, Hamza; Tsarenko, Aleksei; Backenköhler, Michael; Hamed, Mostafa M.; Diamanti, Eleonora; Volkamer, Andrea; Slotboom, Dirk J.; Hirsch, Anna K. H.

doi:10.1039/d3cc04738e

Cited by 3 publications

(1 citation statement)

References 18 publications

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“…[2][3][4] Recent literature highlights the application of new targets, analytical methods, and reaction types for tdDCC, resulting in robust protocols and an increasing number of success stories. [5][6][7][8] One of the frequently used reactions in tdDCC is the formation of acylhydrazones from aldehydes and hydrazides. In 2021, we applied this reaction to DXPS, the first enzyme of the 2C-methyl-D-erythritol 4-phosphate (MEP) pathway obtaining promising new anti-infective compounds.…”

Section: Introductionmentioning

confidence: 99%

Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium Tuberculosis IspE

Braun-Cornejo,

Ornago,

Sonawane

et al. 2024

Preprint

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In the search for new antitubercular compounds, we leveraged target-directed dynamic combinatorial chemistry (tdDCC) as an efficient hit-identification method. In tdDCC, the target selects its own binders from a dynamic library generated in situ, reducing the number of compounds that require synthesis and evaluation. We combined a total of twelve hydrazides and six aldehydes to generate 72 structurally diverse N-acylhydrazones. To amplify the best binders, we employed anti-infective target 4-diphosphocytidyl-2C-methyl-D-erythritol kinase (IspE) from Mycobacterium tuberculosis (Mtb). We successfully validated the use of tdDCC as hit-identification method for IspE and optimised the analysis of tdDCC hit determination. From the 72 possible N-acylhydrazones, we synthesised twelve of them revealing several new starting points for the development of IspE inhibitors as antibacterial agents.

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Section: Introductionmentioning

confidence: 99%

Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium Tuberculosis IspE

Braun-Cornejo,

Ornago,

Sonawane

et al. 2024

Preprint

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Target repurposing unravels avermectins and derivatives as novel antibiotics inhibiting energy‐coupling factor transporters (ECFTs)

Haupenthal,

Rafehi,

Kany

et al. 2024

Archiv der Pharmazie

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Energy‐coupling factor transporters (ECFTs) are membrane‐bound ATP‐binding cassette (ABC) transporters in prokaryotes that are found in pathogens against which novel antibiotics are urgently needed. To date, just 54 inhibitors of three molecular‐structural classes with mostly weak inhibitory activity are known. Target repurposing is a strategy that transfers knowledge gained from a well‐studied protein family to under‐studied targets of phylogenetic relation. Forty‐eight human ABC transporters are known that may harbor structural motifs similar to ECFTs to which particularly multitarget compounds may bind. We assessed 31 multitarget compounds which together target the entire druggable human ABC transporter proteome against ECFTs, of which nine showed inhibitory activity (hit rate 29.0%) and four demonstrated moderate to strong inhibition of an ECFT (IC50 values between 4.28 and 50.2 µM) as well as antibacterial activity against ECFT‐expressing Streptococcus pneumoniae. Here, ivermectin was the most potent candidate (MIC95: 22.8 µM), and analysis of five ivermectin derivatives revealed moxidectin as one of the most potent ECFT‐targeting antibacterial agents (IC50: 2.23 µM; MIC95: 2.91 µM). Distinct molecular‐structural features of avermectins and derivatives as well as the differential biological response of the hit compounds in general provided first indications with respect to the structure–activity relationships and mode of action, respectively.

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An energy coupling factor transporter ofStreptococcus sanguinisimpacts antibiotic susceptibility as well as metal and membrane homeostasis

Rudzite,

O’Toole

2024

Preprint

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Streptococcus sanguinisis a prevalent member of human microbiome capable of acting as a causative agent of oral and respiratory infections.S. sanguiniscompetitive success within the infection niche is dependent on acquisition of metal ions and vitamins. Among the systems that bacteria use for micronutrient uptake is the energy coupling factor (ECF) transporter system EcfAAT. Here we describe physiological changes arising from EcfAAT transporter disruption. We found that EcfAAT contributes toS. sanguinisantibiotic sensitivity as well as metal and membrane homeostasis. Specifically, our work found that disruption of EcfAAT results in increased polymyxin susceptibility. We performed assessment of cell-associated metal content and found depletion of iron, magnesium, and manganese. Furthermore, membrane composition analysis revealed significant enrichment in unsaturated fatty acid species resulting in increased membrane fluidity. Our results demonstrate how disruption of a single EcfAAT transporter can have broad consequences on bacterial cell homeostasis. ECF transporters are of interest within the context of infection biology in bacterial species other than streptococci, hence work described here will further the understanding of how micronutrient uptake systems contribute to bacterial pathogenesis.ImportanceProficiency in micronutrient uptake is key for pathogen success in bacteria-bacteria and bacteria-host interactions within the infection context. Micronutrient uptake mechanisms are of interest in furthering the understanding of bacterial physiology within infection niche and as targets for design of antimicrobials. Here we describe how a deletion of a nutrient uptake transporter inS. sanguinisalters bacterial sensitivity to antibiotics. We also show that a defect in this candidate nutrient uptake system has consequences on the intracellular metal content, and also results in changes in membrane fatty acid composition and fluidity. This study demonstrates how disruption of a single nutrient uptake system disrupts bacterial physiology resulting in increased antibiotic sensitivity.

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Hit optimization by dynamic combinatorial chemistry on Streptococcus pneumoniae energy-coupling factor transporter ECF-PanT

Abstract: First application of dynamic combinatorial chemistry to the whole complex of the energy-coupling factor transporter PanT from Streptococcus pneumoniae.

Cited by 3 publications

References 18 publications

Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium Tuberculosis IspE

Target-Directed Dynamic Combinatorial Chemistry Affords Binders of Mycobacterium Tuberculosis IspE

Target repurposing unravels avermectins and derivatives as novel antibiotics inhibiting energy‐coupling factor transporters (ECFTs)

An energy coupling factor transporter ofStreptococcus sanguinisimpacts antibiotic susceptibility as well as metal and membrane homeostasis

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