Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY.

The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.

ß-Hydroxylation of α-amino-ß-hydroxylbutanoyl-glycyluridine catalyzed by a nonheme hydroxylase ensures the maturation of caprazamycin.

Caprazamycin is a nucleoside antibiotic that inhibits phospho-N-acetylmuramyl-pentapeptide translocase (MraY). The biosynthesis of nucleoside antibiotics has been studied but is still far from completion. The present study characterized enzymes Cpz10, Cpz15, Cpz27, Mur17, Mur23 out of caprazamycin/muraymycin biosynthetic gene cluster, particularly the nonheme αKG-dependent enzyme Cpz10. Cpz15 is a ß-hydroxylase converting uridine mono-phosphate to uridine 5' aldehyde, then incorporating with threonine by Mur17 (Cpz14) to form 5'-C-glycyluridine. Cpz10 hydroxylates synthetic 11 to 12 in vitro. Major product 13 derived from mutant Δcpz10 is phosphorylated by Cpz27. ß-Hydroxylation of 11 by Cpz10 permits the maturation of caprazamycin, but decarboxylation of 11 by Mur23 oriented to muraymycin formation. Cpz10 recruits two iron atoms to activate dioxygen with regio-/stereo-specificity and commit electron/charge transfer, respectively. The chemo-physical interrogations should greatly advance our understanding of caprazamycin biosynthesis, which is conducive to pathway/protein engineering for developing more effective nucleoside antibiotics.

Effects of storytelling on the childhood brain: near-infrared spectroscopic comparison with the effects of picture-book reading.

In children, storytelling provides many psychological and educational benefits, such as enhanced imagination to help visualize spoken words, improved vocabulary, and more refined communication skills. However, the brain mechanisms underlying the effects of storytelling on children are not clear. In this study, the effects of storytelling on the brains of children were assessed by using near-infrared spectroscopy (NIRS). Results indicated significant decreases of the blood flow in the bilateral prefrontal areas during picture-book reading when the subjects were familiarized in comparison to the cases of the subject naïve to the stories. However, no significant differences in the blood flow were found during storytelling between the subjects naïve and familiarized to the stories. The results indicated more sustained brain activation to storytelling in comparison with picture-book reading, suggesting possible advantages of storytelling as a psychological and educational medium in children.