Synthesis and biological evaluation of solithromycin analogs against multidrug resistant pathogens

Daher, Samer S.; Jin, Xiao; Patel, Jignesh; Freundlich, Joel S.; Buttaro, Bettina A.; Andrade, Rodrigo

doi:10.1016/j.bmcl.2019.03.038

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…22a Since both oxazolidinones and macrolides bind deep within the large ribosomal subunit in fairly occluded binding sites, siderophore conjugates without cleavable linkers have been met with limited success, potentially due to interference of the linkers with binding. 12,21,36,88,89 Our strategy would avoid this complication by enabling release of the parent antibiotics.…”

Section: ■ Resultsmentioning

confidence: 99%

“…We also chose two ribosomal protein synthesis inhibitors, amino-oxazolidinone 5 and solithromycin 6 , as examples of antibiotics that must gain access to the cytoplasm to be active . Since both oxazolidinones and macrolides bind deep within the large ribosomal subunit in fairly occluded binding sites, siderophore conjugates without cleavable linkers have been met with limited success, potentially due to interference of the linkers with binding. ,,,, Our strategy would avoid this complication by enabling release of the parent antibiotics.…”

Section: Resultsmentioning

confidence: 99%

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Platform to Discover Protease-Activated Antibiotics and Application to Siderophore–Antibiotic Conjugates

et al. 2020

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Here we present a platform for discovery of protease-activated prodrugs and apply it to antibiotics that target Gram-negative bacteria. Because cleavable linkers for prodrugs had not been developed for bacterial proteases, we used substrate phage to discover substrates for proteases found in the bacterial periplasm. Rather than focusing on a single protease, we used a periplasmic extract of E. coli to find sequences with the greatest susceptibility to the endogenous mixture of periplasmic proteases. Using a fluorescence assay, candidate sequences were evaluated to identify substrates that release native amine-containing payloads. We next designed conjugates consisting of (1) an N-terminal siderophore to facilitate uptake, (2) a protease-cleavable linker, and (3) an amine-containing antibiotic. Using this strategy, we converted daptomycinwhich by itself is active only against Gram-positive bacteriainto an antibiotic capable of targeting Gram-negative Acinetobacter species. We similarly demonstrated siderophore-facilitated delivery of oxazolidinone and macrolide antibiotics into a number of Gram-negative species. These results illustrate this platform’s utility for development of protease-activated prodrugs, including Trojan horse antibiotics.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore–Antibiotic Conjugates

et al. 2020

View full text Add to dashboard Cite

show abstract

“…22a Since both oxazolidinones and macrolides bind deep within the large ribosomal subunit in fairly occluded binding sites, siderophore conjugates without cleavable linkers have been met with limited success, potentially due to interference of the linkers with binding. 12,21,37,106,107 Our strategy would avoid this complication by enabling release of the parent antibiotics.…”

Section: Substrate Phage Display Leads To Wspkym-rfg and Wswc-kwasg Amentioning

confidence: 99%

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates

Boyce

Dang²,

Ary³

et al. 2020

Preprint

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Here we present a platform for discovery of protease-activated prodrugs and apply it to antibiotics that target Gram-negative bacteria. Because cleavable linkersfor prodrugs had not been developed for bacterial proteases, we used substrate phage to discover substrates for proteases found in the bacterial periplasm. Rather than focusing on a single protease, we used a periplasmic extract to find sequences with the greatest susceptibility to the endogenous mixture of periplasmic proteases. Using a fluorescence assay, candidate sequences were evaluated to identify substrates that release native amine-containing payloads without an attached peptide “scar”. We next designed conjugates consisting of: 1) an N-terminal siderophore to facilitate uptake; 2) a protease-cleavable linker; 3) an amine-containing antibiotic. Using this strategy, we converted daptomycin – which by itself is active only against Gram-positive bacteria – into an antibiotic capable of targeting Gram-negative Acinetobacter species. We similarly demonstrated siderophorefacilitated delivery of oxazolidinone and macrolide antibiotics into a number of Gram-negative species. These results illustrate this platform’s utility for development of protease-activated prodrugs, including Trojan horse antibiotics.

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“…Solithromycin ( D , Figure 1 ) is a powerful 2-fluoroantibiotic that can be prepared by click chemistry from the azide 17 and 3-ethynylaniline. The (3 + 2) dipolar cycloaddition is effected by Cu(I)-catalysis ( Scheme 6 ) [ 13 , 14 ]. The catalyst is generated in situ from CuSO 4 , sodium ascorbate, and the terminal alkyne in t BuOH:water (1:1) at rt, 24 h, yield 70–90% of the anti-(1,4)-triazole 19 .…”

Section: Synthesismentioning

confidence: 99%

“…The catalyst is generated in situ from CuSO 4 , sodium ascorbate, and the terminal alkyne in t BuOH:water (1:1) at rt, 24 h, yield 70–90% of the anti-(1,4)-triazole 19 . 2-Fluoro-11-pendent-ω-azidobutyl-ketolides such as the azide 17 is converted to 4-substituted [1,2,3]-triazole as a single regional isomer by reaction with the corresponding acetylene to afford 2-fluoro-ketolide 19 [ 13 ] . Hetaryl derivatives such as 3-thienyl derivatives are prepared in the same manner.…”

Section: Synthesismentioning

confidence: 99%

Scaffold Modifications in Erythromycin Macrolide Antibiotics. A Chemical Minireview

Undheim

2020

Molecules

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Clarithromycin and congeners are important antibacterial members of the erythromycin A 14-membered macrocyclic lactone family. The macrolide scaffold consists of a multifunctional core that carries both chemically reactive and non-reactive substituents and sites. Two main approaches are used in the preparation of the macrolides. In semisynthesis, the naturally occurring macrocycle serves as a substrate for structural modifications of peripheral substituents. This review is focused on substituents in non-activated positions. In the total synthesis approach, the macrolide antibiotics are constructed by a convergent assembly of building blocks from presynthesized substrates or substrates prepared by biogenetic engineering. The assembled block structures are linear chains that are cyclized by macrolactonization or by metal-promoted cross-coupling reactions to afford the 14-membered macrolactone. Pendant glycoside residues are introduced by stereoselective glycosylation with a donor complex. When available, a short summary of antibacterial MIC data is included in the presentations of the structural modifications discussed.

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Synthesis and biological evaluation of solithromycin analogs against multidrug resistant pathogens

Cited by 8 publications

References 34 publications

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore–Antibiotic Conjugates

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore–Antibiotic Conjugates

Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates

Scaffold Modifications in Erythromycin Macrolide Antibiotics. A Chemical Minireview

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