Polycyclic Polyprenylated Acylphloroglucinols: An Emerging Class of Non‐Peptide‐Based MRSA‐ and VRE‐Active Antibiotics

Guttroff, Claudia; Baykal, Aslihan; Wang, Huanhuan; Popella, Peter; Kraus, Frank; Biber, Nicole; Krauss, Sophia; Götz, Friedrich; Plietker, Bernd

doi:10.1002/anie.201707069

Cited by 43 publications

(30 citation statements)

References 49 publications

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“…Due to the structural similarities between hyperforin and the hop bitter acids (humulone, lupulone and their derivatives), it has been speculated that their biosynthetic pathways might be genetically and biochemically related (Ciochina & Grossman, 2006;Guttroff et al, 2017). We performed a BLAST search using the PKS sequence from hops HlVPS (Okada & Ito, 2001), which is involved in the biosynthesis of hop bitter acids, with the genome of H. perforatum.…”

Section: Discovery Of Putative Biosynthetic Gene Clusters In Genome O...mentioning

confidence: 99%

Convergent gene clusters underpin hyperforin biosynthesis in St John's wort

Morotti

Wang

et al. 2022

New Phytologist

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Summary The meroterpenoid hyperforin is responsible for the antidepressant activity of St John's wort extracts, but the genes controlling its biosynthesis are unknown. Using genome mining and biochemical work, we characterize two biosynthetic gene clusters (BGCs) that encode the first three steps in the biosynthesis of hyperforin precursors. The findings of syntenic and phylogenetic analyses reveal the parallel assembly of the two BGCs. The syntenous BGC in Mesua ferrea indicates that the first cluster was assembled before the divergence of the Hypericaceae and Calophyllaceae families. The assembly of the second cluster is the result of a coalescence of genomic fragments after a major duplication event. The differences between the two BGCs – in terms of gene expression, response to methyl jasmonate, substrate specificity and subcellular localization of key enzymes – suggest that the presence of the two clusters could serve to generate separate pools of precursors. The parallel assembly of two BGCs with similar compositions in a single plant species is uncommon, and our work provides insights into how and when these gene clusters form. Our discovery helps to advance our understanding of the evolution of plant specialized metabolism and its genomic organization. Additionally, our results offer a foundation from which hyperforin biosynthesis can be more fully understood, and which can be used in future metabolic engineering applications.

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Section: Discovery Of Putative Biosynthetic Gene Clusters In Genome O...mentioning

confidence: 99%

Convergent gene clusters underpin hyperforin biosynthesis in St John's wort

Morotti

Wang

et al. 2022

New Phytologist

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“…[ 9‐10 ] In recent years, a series of novel PPAPs with intriguing structures and important biological activities have attracted great interest in the synthesis and biology fields. [ 11‐15 ] Hypericum monogynum Linn was used as a traditional Chinese medicine for the treatment of hepatitis, conjunctivitis, acute laryngopharyngitis, and snake bites. [ 16 ] During our continuous research for structurally novel and biologically valuable PPAPs, [ 17‐19 ] eleven biogenetically related polyprenylated acylphloroglucinols (PPAPs) with diverse structures (Figure 1), including four novel PPAPs ( 1 — 4 ) and five new compounds ( 5 — 9 ), were isolated from the flowers of H. monogynum .…”

Section: Background and Originality Contentmentioning

confidence: 99%

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Zeng

Yang

et al. 2021

Chin. J. Chem.

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Main observation and conclusion Eleven biogenetically related polyprenylated acylphloroglucinols (PPAPs), including four novel skeletons (1—4) and five new compounds (5—9), were isolated from the flowers of Hypericum monogynum. Hypermonones A—D (1—4) represented the first example of a unique dilactone structure containing carbonyl bonded single δ‐lactone and tricyclic γ‐lactone moieties. Their structures were elucidated by NMR analysis, X‐ray crystallography, and ECD calculations. Moreover, we revised the structure of hyperibrin B to hypermonone I (9) via NMR analysis, a quantum computational chemistry method, and hypothetic biosynthetic considerations. Three compounds (5, 6, and 9) with significant MDR reversal activity (RF ranging from 61 to 223) were superior to the positive control verapamil (MCF‐7/ADR, RF: 53; HepG2/ADR, RF: 124). Mechanism study for compound 5 indicated that this compound could inhibit the function of P‐gp transport rather than its expression, and the possible recognition mechanism between compound 5 and P‐gp was predicted by molecular docking.

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“…Since PPAP 23 exhibited a comparable MIC to the MRSA USA300 as vancomycin (Guttroff et al, 2017), we then compared its efficacy on killing mid-exponential S. aureus USA300 and biofilm cells of S. aureus SA 113 with vancomycin. PPAP 23 eradicated the mid-exponential population of S. aureus by 8 logs to the limit of detection at 100× MIC in 48 h, whereas the same concentration of vancomycin led to only 3-log reduction in the population of mid-exponential cells (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…The concept of separating framework construction from framework decoration led to a major breakthrough in the chemical synthesis of distinct endo -type B PPAPs (Biber et al, 2011). This synthetic approach laid the foundation for the synthesis of a large number of endo -type B PPAP variants (Guttroff et al, 2017). These variants were investigated for their antimicrobial activity and cytotoxicity in comparison with hyperforin and vancomycin.…”

Section: Introductionmentioning

confidence: 99%

“…PPAP 23 showed a half maximal inhibitory concentration (IC 50 ) of 96 μg/ml for human monocytic HL-60 cells, which was 15-fold less toxic than hyperforin. Moreover, PPAP 23 is photochemically stable (Guttroff et al, 2017). Since the mode of action remains unknown, we chose PPAP 23 to further investigate its antimicrobial activity and underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus

et al. 2019

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Recently, a series of endo-type B polycyclic polyprenylated acylphloroglucinols (PPAP) derivatives with high antimicrobial activities were chemically synthesized. One of the derivatives, PPAP 23, which showed high antimicrobial activity and low cytotoxicity, was chosen for further investigation of its bactericidal profiles and mode of action. PPAP 23 showed a better efficacy in killing methicillin resistant Staphylococcus aureus (MRSA) and decreasing the metabolic activity of 5-day-old biofilm cells than vancomycin. Moreover, S. aureus did not appear to develop resistance against PPAP 23. The antimicrobial mechanism of PPAP 23 was investigated by RNA-seq combined with phenotypic and biochemical approaches. RNA-seq suggested that PPAP 23 signaled iron overload to the bacterial cells because genes involved in iron transport were downregulated and iron storage gene was upregulated by PPAP 23. PPAP 23 affected the membrane integrity but did not induce pore formation; it inhibited bacterial respiration. PPAP 23 preferentially inhibited Fe–S cluster enzymes; it has a mild iron chelating activity and supplementation of exogenous iron attenuated its antimicrobial activity. PPAP 23 was more effective in inhibiting the growth of S. aureus under iron-restricted condition. The crystal structure of a benzylated analog of PPAP 23 showed a highly defined octahedral coordination of three PPAP ligands around a Fe (3+) core. This suggests that PPAPs are generally capable of iron chelation and are able to form defined stable complexes. PPAP 23 was found to induce reactive oxygen species (ROS) and oxidative stress. Fluorescence microscopic analysis showed that PPAP 23 caused an enlargement of the bacterial cells, perturbed the membrane, and dislocated the nucleoid. Taken together, we postulate that PPAP 23 interacts with the cytoplasmic membrane with its hydrophobic pocket and interferes with the iron metabolism to exert its antimicrobial activity in Staphylococcus aureus.

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Polycyclic Polyprenylated Acylphloroglucinols: An Emerging Class of Non‐Peptide‐Based MRSA‐ and VRE‐Active Antibiotics

Cited by 43 publications

References 49 publications

Convergent gene clusters underpin hyperforin biosynthesis in St John's wort

Convergent gene clusters underpin hyperforin biosynthesis in St John's wort

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

The Polycyclic Polyprenylated Acylphloroglucinol Antibiotic PPAP 23 Targets the Membrane and Iron Metabolism in Staphylococcus aureus

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