The gut microbiota is important in the pathogenesis of energy-metabolism related diseases. We focused on the interaction between intestinal bacteria and orally administered chemical drugs. Oral administration of berberine (BBR) effectively treats patients with metabolic disorders. However, because BBR exhibits poor solubility, its absorption mechanism remains unknown. Here, we show that the gut microbiota converts BBR into its absorbable form of dihydroberberine (dhBBR), which has an intestinal absorption rate 5-fold that of BBR in animals. The reduction of BBR to dhBBR was performed by nitroreductases of the gut microbiota. DhBBR was unstable in solution and reverted to BBR in intestine tissues via oxidization. Heat inactivation of intestinal homogenate did not inhibit dhBBR oxidization, suggesting the process a non-enzymatic reaction. The diminution of intestinal bacteria via orally treating KK-Ay mice with antibiotics decreased the BBR-to-dhBBR conversion and blood BBR; accordingly, the lipid- and glucose-lowering efficacy of BBR was reduced. Conclusively, the gut microbiota reduces BBR into its absorbable form of dhBBR, which then oxidizes back to BBR after absorption in intestine tissues and enters the blood. Thus, interaction(s) between the gut microbiota and orally administrated drugs may modify the structure and function of chemicals and be important in drug investigation.

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A PCR-based genetic screening experiment targeting the dTDP-glucose-4,6-dehydratase gene revealed that a marine sediment-derived strain, Streptomyces sp. 7-145, had the potential to produce glycosidic antibiotics. Chemical investigation of culture extracts of this strain yielded two new 6-deoxyhexose-containing antibiotics, 11',12'-dehydroelaiophylin (1) and 11,11'-O-dimethyl-14'-deethyl-14'-methylelaiophylin (2), together with four known elaiophylin analogues (3-6). Their structures were determined by extensive NMR, MS, and CD analyses. Compounds 1, 3, 4, and 6 showed good antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci pathogens.

In this paper, 26 natural polymyxin components and a new derivative S were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E, E-Val, A, M, D, and S showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E, M, and S was similar to that of polymyxin E. Compound S, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S could be a new drug candidate.

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