Semisynthesis and Biological Evaluation of Platensimycin Analogues with Varying Aminobenzoic Acids

Tian, Kai; Deng, Youchao; Qiu, Lin; Zhu, Xia; Shen, Ben; Duan, Yanwen; Huang, Yong

doi:10.1002/slct.201802475

Cited by 9 publications

(10 citation statements)

References 44 publications

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“… [13] Total synthesis of platencin[ 22 , 23 ] and platensimycin[ 24 , 25 ] have been carried out, and efforts have been undertaken to increase the antibiotic activity through synthesis of analogues. For platensimycin, this includes the modifications of the benzoic acid head group[ 26 , 27 ] and the tetracyclic cage. [ 28 , 29 , 30 , 31 , 32 ] While some of these compounds showed promising activity against Gram‐positive bacteria, for most compounds activity against Gram‐negative bacteria was not reported.…”

Section: Introductionmentioning

confidence: 99%

An Experimental Toolbox for Structure‐Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics

et al. 2021

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FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry (BLI) as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening a library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.

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Section: Introductionmentioning

confidence: 99%

An Experimental Toolbox for Structure‐Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics

et al. 2021

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“…[23] Total syntheses of platencin [24,25] and platensimycin [26,27] have been carried out, and efforts have been undertaken to increase the antibiotic activity through synthesis of analogues. For platensimycin this includes the modifications of the benzoic acid head group [28,29] and the tetracyclic cage. [30][31][32][33][34] While some of these compounds showed promising activity against Gram-positive bacteria, for most compounds the potency activity against Gram-negative bacteria was not reported.…”

Section: Introductionmentioning

confidence: 99%

An Experimental Toolbox for Structure-Based Hit Discovery for P. Aeruginosa FabF, a Promising Target for Antibiotics

Espeland¹,

Georgiou²,

Klein³

et al. 2021

Preprint

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FabF (3-oxoacyl-[acyl-carrier-protein] synthase 2), which catalyses the rate limiting condensation reaction in the fatty acid synthesis II pathway, is an attractive target for new antibiotics. Here, we focus on FabF from P. aeruginosa (PaFabF) as antibiotics against this pathogen are urgently needed. To facilitate exploration of this target we have set up an experimental toolbox consisting of binding assays using bio-layer interferometry as well as saturation transfer difference (STD) and WaterLOGSY NMR in addition to robust conditions for structure determination. The suitability of the toolbox to support structure-based design of FabF inhibitors was demonstrated through the validation of hits obtained from virtual screening. Screening of our in-house library of almost 5 million compounds resulted in 6 compounds for which binding into the malonyl-binding site of FabF was shown. For one of the hits, the crystal structure in complex with PaFabF was determined. Based on the obtained binding mode, analogues were designed and synthesised, but affinity could not be improved. This work has laid the foundation for structure-based exploration of PaFabF.

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Section: Introdutctionmentioning

confidence: 99%

“… It was regarded as a milestone discovery due to its unprecedented molecular structure and novel mode of action against FabB/FabF from bacterial fatty acid biosynthesis as well as the powerful whole-cell screening strategy using 250 000 crude natural product extracts . Although the poor pharmacokinetics (PK) of PTM, namely its rapid renal clearance, limits its clinical application as a potential antibiotic, the generation of dozens of PTM analogues through total synthesis, semi-synthesis, and biosynthesis has revealed critical new insights into its structure–activity relationships. − …”

Section: Introductionmentioning

confidence: 99%

“…13 While the poor pharmacokinetics (PK) of PTM, namely its rapid renal clearance, 14 limits its clinical application as potential antibiotics, the generation of dozens of PTM analogues through total synthesis, semi-synthesis and biosynthesis, has revealed critical new insights into its structure-activity relationships. [14][15][16][17][18][19][20][21][22][23][24][25] We recently reported a series of PTM thioether-analogues with promising antibacterial activities against MRSA, through a biomimetic sulfur-Michael addition strategy. 23 Those sulfur analogues could undergo a β-elimination reaction, which resulted in PTM in an aqueous buffer.…”

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Evaluation of Platensimycin and Platensimycin-Inspired Thioether Analogues against Methicillin-Resistant Staphylococcus aureus in Topical and Systemic Infection Mouse Models

Qiu

Deng

et al. 2019

Mol. Pharmaceutics

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Staphylococcus aureus is one of the most common pathogens for hospital-acquired and community-acquired infections. Methicillin-resistant S. aureus (MRSA) formed biofilms in wounds are difficult to treat with conventional antibiotics. By targeting FabB/FabF of bacterial fatty acid synthases, platensimycin (PTM) was discovered as a promising natural antibiotic against MRSA infections. In this study, PTM and its previously synthesized sulfur-Michael derivative PTM-2t, could reduce over 95% biofilm formation from S. aureus ATCC 29213 when used at 2 μg/mL in vitro. Topical application of ointments containing PTM or PTM-2t (2 × 4 mg/day/mouse) was successfully used to treat MRSA infections in a BABL/c mouse wound burn model. As a potential prodrug lead, PTM-2t showed improved in vivo efficacy in a mouse peritonitis model, compared to PTM. Our study suggests that PTM and its analogue may be used topically or locally to treat bacterial infections. In addition, the use of prodrug strategies might be instrumental to improve the poor pharmacokinetics properties of PTM.

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Semisynthesis and Biological Evaluation of Platensimycin Analogues with Varying Aminobenzoic Acids

Cited by 9 publications

References 44 publications

An Experimental Toolbox for Structure‐Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics

An Experimental Toolbox for Structure‐Based Hit Discovery for P. aeruginosa FabF, a Promising Target for Antibiotics

An Experimental Toolbox for Structure-Based Hit Discovery for P. Aeruginosa FabF, a Promising Target for Antibiotics

Evaluation of Platensimycin and Platensimycin-Inspired Thioether Analogues against Methicillin-Resistant Staphylococcus aureus in Topical and Systemic Infection Mouse Models

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