Deposits of clastic carbonate-dominated (calciclastic) sedimentary slope systems in the rock record have been identified mostly as linearly-consistent carbonate apron deposits, even though most ancient clastic carbonate slope deposits fit the submarine fan systems better. Calciclastic submarine fans are consequently rarely described and are poorly understood. Subsequently, very little is known especially in mud-dominated calciclastic submarine fan systems. Presented in this study are a sedimentological core and petrographic characterisation of samples from eleven boreholes from the Lower Carboniferous of Bowland Basin (Northwest England) that reveals a >250 m thick calciturbidite complex deposited in a calciclastic submarine fan setting. Seven facies are recognised from core and thin section characterisation and are grouped into three carbonate turbidite sequences. They include: 1) Calciturbidites, comprising mostly of highto low-density, wavy-laminated bioclast-rich facies; 2) low-density densite mudstones which are characterised by planar laminated and unlaminated muddominated facies; and 3) Calcidebrites which are muddy or hyper-concentrated debrisflow deposits occurring as poorly-sorted, chaotic, mud-supported floatstones. These

Phd by thesis

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.

biotics of the penicillin and cephalosporin families, 3,4 as well as the glycopeptides of the vancomycin family 5 (Figure 1a). * To whom correspondence should be addressed: christopher_walsh@ hms.harvard.edu. † Harvard Medical School. ‡ Harvard University. Christopher T. Walsh is the Hamilton Kuhn Professor of Biological Chemistry and Molecular Pharmacology (BCMP) at Harvard Medical School. He has had extensive experience in academic administration, including Chairmanship of the MIT Chemistry Department (1982−1987) and the HMS Biological Chemistry & Molecular Pharmacology Department (1987−1995) as well as serving as President and CEO of the Dana Farber Cancer Institute (1992−1995). His research has focused on enzymes and enzyme inhibitors, with recent specialization on antibiotics. He and his group have authored over 590 research papers, a text (Enzymatic Reaction Mechanisms), and two books (Antibiotics: Origins, Actions, Resistance and Posttranslational Modification of Proteins: Expanding Nature’s Inventory). He is a member of the National Academy of Sciences, the Institute of Medicine, and the American Philosophical Society.

Assembly-line enzymology for polyketide and nonribosomal Peptide antibiotics: logic, machinery, and mechanisms.

Summary: The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

Challenges of Antibacterial Discovery

Transannular disulfide functions as a key structural element imparting diverse biological activities of epidithiodiketopiperazines (ETPs). Although previous studies proposed mechanisms, α, β'-disulfide formation in ETPs is not well determined owing to the lack of identification for the hypothetical intermediate. Here, we characterize the key ortho-quinone methide (o-QM) intermediate and prove its involvement in the carbon-sulfur migration from α, α'- to α, β'-disulfide by elucidating pretrichodermamide A biosynthesis, which is catalyzed by a FAD-dependent thioredoxin oxygenase TdaE harboring a noncanonical CXXQ motif. Biochemical investigations of recombinant TdaE and mutants demonstrated that the construction of α, β'-disulfide was initiated by Gln140-triggering proton abstraction for generation of the essential o-QM intermediate, accompanied by β'-acetoxy elimination. Subsequent attack on α, α'-disulfide by Cys137 led to disulfide migration and spiro-furan formation. This study expands the biocatalytic toolbox for transannular disulfide formation and set the stage for targeted discovery of bioactive ETPs.

An ortho-Quinone Methide Mediates Disulfide Migration in the Biosynthesis of Epidithiodiketopiperazines.

Four undescribed plant growth inhibitory indole derivatives, colletotriauxins A-D (1-4), along with two known analogues indole-3-acetic acid (IAA) (5) and its amide indole-3-acetamide (6), were isolated from the phytopathogenic fungus Colletotrichum gloeosporioides NRRL 45420. Their structures were elucidated by NMR and MS analyses. 1 and 2 are rhamnosides of indole-3-ethanol (tryptophol) and its methylated derivative, respectively. In the structures of 3 and 4, the two terminal hydroxyl groups of hexitol and pentane-1,2,3,4,5-pentol are connected with indole-3-(2-methyl)-acetyl and acetyl moieties. Compounds 1-6 inhibit Lepidium sativum seedling growth. The inhibition activities of colletotriauxins for stem growth were even stronger than IAA, with compounds 3 and 4 as the most active ones. These results suggested that colletotriauxins could serve as potential candidates as herbicides.

Colletotriauxins A-D, New Plant Growth Inhibitors from the Phytopathogenic Fungus Colletotrichum gloeosporioides.

Formation of Fungal 2,18-Dioxo-2,18-seco Indole Diterpenes by Nonenzymatic Flavin-Catalyzed Oxidative Ring Expansion and Oxygen Incorporation from Solvent Water.

The highly oxygenated indole alkaloid speradine F (4) with a 6/5/6/5/5/5 hexacyclic skeleton was isolated from a culture of Penicillium palitans, together with its precursors β-cyclopiazonic acid (β-CPA, 5) and cyclopiazonic acid (CPA, 1). Gene deletion and heterologous expression led to the identification of the responsible five-gene spe cluster for the speradine skeleton formation. Precursor supply experiments proved that 1 was enzymatically converted, via 2-oxoCPA (2), to speradine A (3), which subsequently undergoes multistep nonenzymatic hydroxylations to 4.

Formation of the Fungal Indole Alkaloid Speradine F Implies Multiple Nonenzymatic Oxidation Steps.

Three new antibiotics, vanillobiocin, isovanillobiocin and declovanillobiocin, were isolated from the culture broth of a cloQ-defective mutant of the clorobiocin producer Streptomyces roseochromogenes, which is blocked in the biosynthesis of the prenylated 4-hydroxybenzoic acid moiety of clorobiocin. Spectroscopic analysis showed that the isolated compounds were similar to clorobiocin, but contained vanillic acid as the acyl component instead of the prenylated 4-hydroxybenzoic acid present in clorobiocin. Isovanillobiocin differs from vanillobiocin by the position of the pyrrole unit attached to the sugar moiety of the antibiotic. Declovanillobiocin lacks the chlorine atom at the aminocoumarin ring. All three compounds had lower antibiotic activity against Bacillus subtilis than clorobiocin.

Shu-Ming Li

Papers

An ortho-Quinone Methide Mediates Disulfide Migration in the Biosynthesis of Epidithiodiketopiperazines.

Colletotriauxins A-D, New Plant Growth Inhibitors from the Phytopathogenic Fungus Colletotrichum gloeosporioides.

Formation of Fungal 2,18-Dioxo-2,18-seco Indole Diterpenes by Nonenzymatic Flavin-Catalyzed Oxidative Ring Expansion and Oxygen Incorporation from Solvent Water.

Formation of the Fungal Indole Alkaloid Speradine F Implies Multiple Nonenzymatic Oxidation Steps.

New Aminocoumarin Antibiotics from a cloQ‐Defective Mutant of the Clorobiocin Producer Streptomyces roseochromogenes DS12.976.