Halogenated Spirotetronates from <i>Actinoallomurus</i>

Mazzetti, Carlo; Ornaghi, Mirko; Gaspari, Eleonora; Parapini, Silvia; Maffioli, Sonia; Sosio, Margherita; Donadio, Stefano

doi:10.1021/np300003n

Cited by 28 publications

(27 citation statements)

References 16 publications

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“…The valuable knowledge obtained from the investigation of the biosynthesis, regulation and natural resistance in the natural host of the old drugs as well as the recent developments within screening and isolation methods, sequencing and genome mining, and analytics potentiate the platforms for drug discovery. For example, the analysis of a relatively underexplored genus of Actinoallomurus led to the discovery of two new spirotetronate polyketide antibiotics NAI414-A and NAI414-B [382].…”

Section: Discussionmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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Actinomycetes are remarkable producers of compounds essential for human and veterinary medicine as well as for agriculture. The genomes of those microorganisms possess several sets of genes (biosynthetic gene cluster (BGC)) encoding pathways for the production of the valuable secondary metabolites. A significant proportion of the identified BGCs in actinomycetes encode pathways for the biosynthesis of polyketide compounds, nonribosomal peptides, or hybrid products resulting from the combination of both polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs). The potency of these molecules, in terms of bioactivity, was recognized in the 1940s, and started the “Golden Age” of antimicrobial drug discovery. Since then, several valuable polyketide drugs, such as erythromycin A, tylosin, monensin A, rifamycin, tetracyclines, amphotericin B, and many others were isolated from actinomycetes. This review covers the most relevant actinomycetes-derived polyketide drugs with antimicrobial activity, including anti-fungal agents. We provide an overview of the source of the compounds, structure of the molecules, the biosynthetic principle, bioactivity and mechanisms of action, and the current stage of development. This review emphasizes the importance of actinomycetes-derived antimicrobial polyketides and should serve as a “lexicon”, not only to scientists from the Natural Products field, but also to clinicians and others interested in this topic.

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Section: Discussionmentioning

confidence: 99%

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Robertsen

Musiol-Kroll

2019

Antibiotics

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“…This finding is consistent with previous reports (Mazzetti et al . ; Ola et al . ), confirm a higher level of antimicrobial activity of these active compounds and also that they were equally effective against MDR clinical isolates of S. pneumoniae .…”

Section: Discussionmentioning

confidence: 99%

In vitroactivity of bioactive extracts from rare actinomycetes against multi-drug resistantStreptococcus pneumoniae

Tiwari

Raj

Upadhyay³

et al. 2015

J Appl Microbiol

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“…Cytotoxicities for human macrovascular endothelial cells and human monocytes in culture ( Fig. 1c, rows 21-22) were determined as described 44 .…”

Section: Antibacterial Activity In Vitromentioning

confidence: 99%

Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase: pseudouridimycin

Maffioli¹,

Degen

Carzaniga

et al. 2017

Preprint

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We screened a library of 3000 Actinobacterial 6 and fungal culture extracts for inhibition of RNAP, and we identified two extracts that inhibited bacterial RNAP (E. coli RNAP) but did not inhibit a structurally unrelated bacteriophage RNAP (SP6 RNAP) and did not contain a previously characterized inhibitor of bacterial RNAP (see Methods). Fractionation of the two extracts by reversed-phase chromatography and structure elucidation of active components by mass spectrometry and 2All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/106906 doi: bioRxiv preprint first posted online Feb. 8, 2017; multidimensional NMR spectrometry revealed that the extracts contained the same novel active component: pseudouridimycin (PUM; Fig. 1a; Extended Data Figs. 1-2).PUM selectively inhibits bacterial RNAP (IC50 = 0.1 μM; selectivity >4-to >500-fold; Fig. 1b; Extended Data Table 1; Extended Data Fig. 3), selectively inhibits bacterial growth (IC50 = 2 to 16 μM; selectivity >6-to >60-fold; Fig. 1c), and clears infection in vivo in a mouse Streptococcus pyogenes peritonitis model (ED50 = 9 mg/kg; Fig. 1c; Extended Data Table 2). PUM exhibits antibacterial activity against both Gram-positive and Gram-negative bacteria and against both drug-sensitive and drug-resistant bacterial strains, including rifamycin-, β-lactam-, fluoroquinolone-macrolide-, tetracycline-, aminoglycoside-, lincosamide-, chloramphenicol-, oxazolidinone-, trimethoprim-, glycopeptide-, lipopeptide-, mupirocin-, and multi-drug-resistant strains (Fig. 1c).PUM exhibits no cross-resistance with the classic RNAP inhibitor Rif (Figs. 1b-c,e), exhibits additive antibacterial activity when co-administered with Rif (Fig. 1f), and exhibits spontaneous resistance rates an order-of-magnitude lower than those of Rif (Fig. 2a), suggesting that PUM inhibits RNAP through a binding site and mechanism different from those of Rif.Gene sequencing indicates that PUM-resistant mutants contain mutations in the rpoB gene (encodes RNAP β subunit) or the rpoC gene (encodes RNAP β′ subunit), confirming that RNAP is the functional cellular target of PUM ( Fig. 2b; Extended Data Fig. 4a-b). In the Gram-positive bacterium S. pyogenes, substitutions conferring ≥4x PUM-resistance are obtained at four sites: β residues 565, 681, and 684, and β′ residue 786 (numbered as in E. coli RNAP; Fig. 2b). In the Gram-negative bacterium E. coli, substitutions conferring PUM-resistance are obtained at two sites: β residues 565 and 681 (Extended Data Fig. 4a-b). The number of sites of substitutions conferring PUM-resistance is an order-of-magnitude lower than the number of sites of substitutions conferring Rif-resistance (2 to 4 vs. 25 7-8 ), consistent with, and accounting for, the observation that spontaneous resistance rates for PUM are an order-of-magnitude lower than those for Rif (Fig. 2a). 3All rights reserved...

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Halogenated Spirotetronates from Actinoallomurus

Cited by 28 publications

References 16 publications

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

In vitroactivity of bioactive extracts from rare actinomycetes against multi-drug resistantStreptococcus pneumoniae

Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase: pseudouridimycin

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