Engyodontochones,Antibiotic Polyketides from the Marine Fungus Engyodontium album Strain LF069

Six new ( 2 , 4 – 8 ) and two known polyketides with a basic structure of an anthraquinone‐xanthone were isolated from mycelia and culture broth of the fungus Engyodontium album strain LF069. The structures and relative configurations of these compounds were established by spectroscopic means, and their absolute configurations were defined mainly by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Compounds 2 and 4 – 8 were given the trivial names engyodontochone A ( 2 ) and B–F ( 4 – 8 ). Compounds 5 – 8 represent the first example of a 23,28 seco‐beticolin carbon skeleton. The relative and absolute configurations of two known substances JBIR‐97/98 ( 1 ) and JBIR‐99 ( 3 ) were determined for the first time. All isolated compounds were subjected to bioactivity assays. Compounds 1 – 4 exhibited inhibitory activity against methicillin‐resistant Staphylococcus aureus (MRSA) that was 10‐fold stronger than chloramphenicol.     

Double Pancake Versus Long Chalcogen–Chalcogen Bonds in Six‐Membered C,N,S‐Heterocycles

The double “pancake” bonding in the dimers of the six‐membered heterocycles 1,3‐dithia‐2,4,6‐triazine ( 4 ) and 1,3‐dithia‐2,4‐diazine ( 16 ) were investigated by means of high‐level quantum chemical calculations (B3LYP and CCSD(T)). It was found that the S–S dimers, 20 a and 27 , are not the most stable isomers, but the dimers showing short S?N ( 21 a ) and S?C ( 25 , 28 ) bonds. An investigation of the 5‐phenyl‐1,3‐dithia‐2,4,6‐triazine ( 4 b ) yields that the syn dimer with two S?S bonds (2.57 Å) is the most stable one. In this dimer, the phenyl groups are placed on top of each other. The additional dispersion energy of the phenyl rings causes a stabilization of the syn‐S–S (C_2v‐like) isomer. As a result, two weak albeit relevant single S?S bonds (2.57 Å) are predicted. These findings contradict the recently published concept of double “pancake” bonding in the dimer 4 b ₂.     

Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.     

Pinensins: The First Antifungal Lantibiotics

Lantibiotics (lanthionine‐containing antibiotics) from Gram‐positive bacteria typically exhibit activity against Gram‐positive bacteria. The activity and structure of pinensin A ( 1 ) and B ( 2 ), lantibiotics isolated from a native Gram‐negative producer Chitinophaga pinensis are described. Surprisingly, the pinensins were found to be highly active against many filamentous fungi and yeasts but show only weak antibacterial activity. To the best of our knowledge, lantibiotic fungicides have not been described before. An in‐depth bioinformatic analysis of the biosynthetic gene cluster established the ribosomal origin of these compounds and identified candidate genes encoding all of the enzymes required for post‐translational modification. Additional encoded functions enabled us to build up a hypothesis for the biosynthesis, export, sensing, and import of this intriguing lantibiotic.     

Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships

The bengamides, sponge‐derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half‐life in mice and antitumor efficacy in a melanoma mouse model.     

The Gallides SrRh2Ga2, SrIr2Ga2, and Sr3Ir4Ga4

The gallides SrRh₂Ga₂, SrIr₂Ga₂, and Sr₃Rh₄Ga₄ were obtained from the elements by induction melting and subsequent annealing. They were investigated by powder and single‐crystal X‐ray diffraction: CaRh₂B₂ type, Fddd, a = 573.2(1), b = 1051.3(1), c = 1343.7(2) pm, wR₂ = 0.0218, 398 F² values, 15 variables for SrRh₂Ga₂; a = 576.0(1), b = 1045.5(1), c = 1350.6(3) pm for SrIr₂Ga₂, and Na₃Pt₄Ge₄ type, I$\bar{4}$ 3m, a = 777.4(2) pm, wR₂ = 0.0234, 190 F² values, 11 variables for Sr₃Ir₄Ga₄. The gallides SrRh₂Ga₂ and Sr₃Ir₄Ga₄ exhibit complex, covalently bonded three‐dimensional [Rh₂Ga₂] and [Ir₄Ga₄] networks with short Rh–Ga (241–246 pm) and Ir–Ga (243–259 pm) distances. The strontium atoms fill large cages within these networks. They are coordinated by 8 Rh + 10 Ga in SrRh₂Ga₂ and by 4 Ir + 8 Ga in Sr₃Ir₄Ga₄. The structure of SrRh₂Ga₂ is discussed along with the monoclinic distortion variants HoNi₂B₂ and BaPt₂Ga₂ on the basis of a group‐subgroup scheme.     

Two more pieces of the colibactin genotoxin puzzle from Escherichia coli show incorporation of an unusual 1-aminocyclopropanecarboxylic acid moiety

Colibactin represents a structurally undefined class of bacterial genotoxin inducing DNA damage and genomic instability in mammalian cells, thus promoting tumour development and exacerbating lymphopenia in animal models. The colibactin biosynthetic gene cluster (clb) has been known for ten years and it encodes a hybrid nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) assembly line. Nevertheless, the final chemical product(s) remain unknown. Previously, we and others reported several colibactin pathway-related metabolites including N-myristoyl-d-asparagine (1) as part of a prodrug precursor that is cleaved from the putative precolibactin to form active colibactin by the peptidase ClbP. Herein, we report two new colibactin pathway-related metabolites (2 and 3) isolated from a clbP mutant of the probiotic E. coli Nissle 1917 strain. Their structures were established by HRMS and NMR. Compound 2 shows an additional 4-aminopenatanoic acid moiety with respect to 1, while 3 is characterized by the presence of an unusual 7-methyl-4-azaspiro[2.4]hept-6-en-5-one residue. Moreover, we propose the biosynthetic pathway towards both intermediates on the basis of extensive gene inactivation and feeding experiments. The identification of 2 and 3 provides further insight into colibactin biosynthesis including the involvement and formation of a rare 1-aminocyclopropanecarboxylic acid unit. Thus, our work establishes additional steps of the pathway forming the bacterial genotoxin colibactin.