Juglomycin A

Juglorubin, juglorescein, and juglocombins A/B are naturally occurring naphthoquinone dimers isolated from Streptomyces sp. These dimers are proposed to be biogenetically derived from juglomycin C, a monomeric naphthoquinone isolated from the same Streptomyces sp. In this study, the dimerization of a juglomycin C derivative, a key step in the total syntheses of these natural products, was investigated. Juglorubin was synthesized from the minor product of the dimerization via the formation of the juglocombin A/B stereoisomers. A mechanism for the dimerization reaction as well as a plausible biosynthetic pathway to obtain juglorubin from juglomycin C are proposed. Furthermore, the antibacterial and cytotoxic activities of five synthetic compounds were evaluated. Among the compounds tested in this study, 1'-O-methyljuglocombin B dimethyl ester and juglomycin C exhibited antibacterial activity against Bacillus subtilis. 1'-O-Methyljuglocombin B dimethyl ester and juglomycin C showed cytotoxicity against human colon carcinoma HCT116 cells and human leukemia HL-60 cells. 1'-O-Methyljuglocombin B dimethyl ester exhibited cytotoxicity against human normal MRC-5 cells as strong as that against human cancer cells. In contrast, juglomycin C was less toxic against normal MRC-5 cells, indicating a significant selectivity toward cancer cells.

Aim: To evaluate the antimicrobial potential of Juglomycins isolated from Streptomyces achromogenes E91CS4, an endophyte of Crocus sativus Linn. Methods and results: The extract from E91CS4 displayed significant antimicrobial activity against several pathogens. The endophyte was identified as S. achromogenes on by 16S ribosomal gene analysis. Chemical investigation of the extract led to the isolation of two naphthoquinone antibiotics, Juglomycin A and B. Juglomycin A inhibited several pathogens, with an MIC value of 13·7µg ml-1 , whereas it was most potent against Escherichia coli, Bacillus thuringiensis and Xanthobacter flavus with MIC values of 6·8, 3·4 and 6·8 µg ml-1 respectively. It was found to reduce the biofilm formation in E. coli through inhibition of swimming and swarming motilities and downregulation of fimH gene. The α-haemolysin-related gene (hlyA) was also downregulated indicating that the compound is also reducing the virulence in E. coli. In vitro time kill kinetics showed efficient bactericidal activity of this compound. Furthermore, Juglomycin A inhibited bacterial transcription/translation in vitro, while also inducing postantibiotic effect in E. coli. Conclusions: Juglomycin A is a potential antimicrobial compound against several bacterial pathogens, particularly, E. coli. Significance and impact of the study: This study showed the promising potential of Juglomycin A as an antimicrobial agent. Efforts should be made to scale up the production of this compound and conduct further studies to explore its efficacy as an antibiotic, using in vivo models.

A unified and common intermediate strategy for syntheses of juglomycins and their derivatives is reported. The use of a 1,4-dimethoxynaphthalene derivative as a key intermediate enabled easy access to various juglomycin derivatives. In this study, juglomycins A-D, juglomycin C amide, khatmiamycin and its 4-epimer, and the structure proposed for juglomycin Z were synthesized from this intermediate. The absolute configuration of natural khatmiamycin has been established to be 3R,4R through our synthesis. Unfortunately, the spectroscopic data for synthetic juglomycin Z were not consistent with the data reported for the natural one, strongly suggesting a structural misassignment.