Total synthesis of structurally diverse pleuromutilin antibiotics

Goethe, Olivia; DiBello, Mikaela; Herzon, Seth B.

doi:10.1038/s41557-022-01027-7

Cited by 22 publications

(13 citation statements)

References 42 publications

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“…We believe that the information provided by the structure of the Cfr-modified ribosome and its complexes with antibiotics is an indispensable starting point for the structure-based development of next-generation drugs active against the most challenging multidrug-resistant pathogens. This quest will likely be stimulated by the recently discovered combinatorial approaches for the synthesis of novel oxepanoprolinamides 33 , streptogramins 39 , pleuromutilins 40 , and other antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion

Aleksandrova,

Wu,

Tresco

et al. 2023

Preprint

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The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacteriumThermus thermophilusand report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.

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Section: Discussionmentioning

confidence: 99%

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion

Aleksandrova,

Wu,

Tresco

et al. 2023

Preprint

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“…Flash chromatography (MeOH:DCM, 8%). Yield: 67 mg (99%, 0.98 mmol); 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 8.14 (br s, 2H), 7.53 (d, J = 1.5 Hz, 1H), 7.38 (dd, J = 7.7, 1.5 Hz, 1H), 7.22 (br s, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.13 (dd, J = 17.8, 11.2 Hz, 1H), 5.58 (d, J = 8.2 Hz, 1H), 5.49−5.23 (m, 4H), 5.12 (dd, J = 17.8, 1.8 Hz, 1H), 5.05 (dd, J = 11.2, 1.8 Hz, 1H), 4.55 (d, J = 6.1 Hz, 1H), 3.94 (s, 3H), 3.42 (t, J = 6.1 Hz, 1H), 2.41 (s, 1H), 2.24−2.00 (m, 4H), 1.68−1.22 (m, 10H), 1.07 (s, 3H), 1.04−0.94 (m, 1H), 0.81 (d, J = 6.9 Hz, 3H), 0.64 (d, J = 6.9 Hz, 3H); 13 6-Amino-9H-purin-9-yl)methyl)-3-hydroxyphenyl)-1H-1,2,3-triazol-1-yl]-22-deoxypleuromutilin (11). General Procedure 1 was applied with azide 8 (20 mg, 0.050 mmol), the alkyne 27 (13.2 mg, 0.050 mmol), sodium ascorbate (2.0 mg, 0.010 mmol), and CuSO 4 (12).…”

Section: Journal Ofmentioning

confidence: 99%

“…The natural product pleuromutilin ( 1 , Figure ), discovered in 1951, , is an attractive foundation for new antibiotics. This is emphasized by the more than 40 pleuromutilin medicinal chemistry and total synthesis articles published within the field over the last 5 years, with some reporting very potent activity and high clinical potential, − and in some cases also by employing novel and unique strategies. ,,,,,− …”

Section: Introductionmentioning

confidence: 99%

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

Heidtmann,

Fejer,

Stærk

et al. 2024

J. Med. Chem.

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Herein, we report the hit-to-lead identification of a drug-like pleuromutilin conjugate 16, based on a triaromatic hit reported in 2020. The lead arose as the clear candidate from a hitoptimization campaign in which Gram-positive antibacterial activity, solubility, and P-gp affinity were optimized. Conjugate 16 was extensively evaluated for its in vitro ADMET performance which, apart from solubility, was overall on par with lefamulin. This evaluation included Caco-2 cell permeability, plasma protein binding, hERG inhibition, cytotoxicity, metabolism in microsomes and CYP3A4, resistance induction, and time-kill kinetics. Intravenous pharmacokinetics of 16 proved satisfactory in both mice and pigs; however, oral bioavailability was limited likely due to insufficient solubility. The in vivo efficacy was evaluated in mice, systemically infected with Staphylococcus aureus, where 16 showed rapid reduction in blood bacteriaemia. Through our comprehensive studies, lead 16 has emerged as a highly promising and safe antibiotic candidate for the treatment of Gram-positive bacterial infections.

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“…This intermediate allowed then access to several members of the mutilin/pleuromutilin family: total syntheses of (+)-12- epi -mutilin, (+)-11,12-di- epi -mutilin, (+)-12- epi -pleuromutilin, (+)-11,12-di- epi -pleuromutilin, and (+)-pleuromutilin ( 1 ) itself were there described in 17 to 20 steps [ 71 – 72 ]. The series was later extended via a revised and improved synthetic strategy toward the tricyclic [5-8-6]-pleuromutilin platform [ 74 ], allowing access to remarkable chemical diversity for pleuromutilin derivatives which were evaluated against a panel of Gram-positive and Gram-negative bacteria ( Scheme 31B ).…”

Section: Reviewmentioning

confidence: 99%

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

Alleman¹,

Gadais²,

Legentil³

et al. 2023

Beilstein J. Org. Chem.

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Terpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diterpenes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki–Hiyama–Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson–Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis.

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Total synthesis of structurally diverse pleuromutilin antibiotics

Cited by 22 publications

References 42 publications

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion

Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion

Hit-to-Lead Identification and Validation of a Triaromatic Pleuromutilin Antibiotic Candidate

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

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