Mutasynthesis generates nine new pyrroindomycins.

Pyrroindomycins (PYRs) represent the only spirotetramate natural products discovered in nature, and possess potent activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Their unique structure and impressive biological activities make them attractive targets for synthesis and biosynthesis; however, the discovery and generation of new PYRs remains challenging. To date, only the initial components A and B have been reported. Herein, we report a mutasynthesis approach for the generation of nine new PYRs with varying acyl modifications on their deoxy-trisaccharide moieties. This was achieved by blocking the formation of the acyl group 1,8-dihydropyrrolo[2,3-b]indole (DHPI) via gene pyrK1 inactivation and supplying chemical acyl precursors. The gene pyrK1 encodes a DUF1864 family protein that probably catalyzes the oxidative transformation of L-tryptophan to DHPI, and its deletion results in the abolishment of DHPI-containing PYRs and the accumulation of three new PYRs either without acyl modification or with DHPI replaced by benzoic acid and pyrrole-2-carboxylic acid. Capitalizing on the capacity of the ΔpyrK1 mutant to produce new PYRs, we have successfully developed a mutasynthesis strategy for the generation of six novel PYR analogs with various aromatic acid modifications on their deoxy-trisaccharide moieties, showcasing the potential for generating structurally diverse PYRs. Overall, this research contributes significantly to understanding the biosynthesis of PYRs and offers valuable perspectives on their structural diversity.

Biocatalytic Steroidal 9α-Hydroxylation and Fragmentation Enable the Concise Chemoenzymatic Synthesis of 9,10-Secosteroids.

9,10-Secosteroids are an important group of marine steroids with diverse biological activities. Herein, we report a chemoenzymatic strategy for the concise, modular, and scalable synthesis of ten naturally occurring 9,10-secosteroids from readily available steroids in three to eight steps. The key feature lies in utilizing a Rieske oxygenase-like 3-ketosteroid 9α-hydroxylase (KSH) as the biocatalyst to achieve efficient C9-C10 bond cleavage and A-ring aromatization of tetracyclic steroids through 9α-hydroxylation and fragmentation. With synthesized 9,10-secosteroides, structure-activity relationship was evaluated based on bioassays in terms of previously unexplored anti-infective activity. This study provides experimental evidence to support the hypothesis that the biosynthetic pathway through which 9,10-secosteroids are formed in nature shares a similar 9α-hydroxylation and fragmentation cascade. In addition to the development of a biomimetic approach for 9,10-secosteroid synthesis, this study highlights the great potential of chemoenzymatic strategies in chemical synthesis.

Therapeutic effects of Buzhong Yiqi decoction in patients with spleen and stomach qi deficiency after routine surgery and chemotherapy for colorectal cancer.

BACKGROUND: According to the theory of traditional Chinese medicine (TCM), the spleen and stomach are the basis of acquired nature and the source of qi and blood biochemistry. After surgery and chemotherapy, patients with colorectal cancer often develop spleen and stomach qi deficiency syndrome, leading to decreased immune function. Buzhong Yiqi decoction, a classic TCM prescription, has the effect of tonifying middle-jiao and invigorating qi, boosting Yang, and suppressing immune-related inflammation. Moreover, it is widely used in the treatment of spleen and stomach qi deficiency syndrome. AIM: To investigate the effect of Buzhong Yiqi decoction on spleen and stomach qi deficiency in patients with colorectal cancer. METHODS: One hundred patients with colorectal cancer who underwent preoperative chemotherapy and laparoscopy at The First TCM Hospital of Changde from January 2022 to October 2023 were retrospectively analyzed. The patients were divided equally into control and observation groups. Both groups underwent conventional rehabilitation surgery, and the observation group was supplemented with Buzhong Yiqi decoction. SPSS 26.0 was used for statistical analyses. The χ 2 test was used for univariate analysis; independent sample t-tests were used in all cases. RESULTS: No significant differences were observed preoperatively in the general characteristics of the two groups. Fourteen days post-surgery, the abdominal distension, emaciation, loose stool, loss of appetite, and vomiting scores were significantly lower in the observation group than in the control group (P < 0.05). Immune function and interleukin (IL)-10 levels in the observation group were significantly higher than those of the control group, whereas IL-6, tumor necrosis factor-α, and C-reactive protein levels, tumor biological indexes, and adverse reactions in the observation group were significantly lower than those of the control group (P < 0.05). One month after surgery, the patients' quality of life in the observation group was significantly higher than that of the patients in the control group (P < 0.05). CONCLUSION: Buzhong Yiqi decoction can regulate inflammatory responses and metabolic processes by enhancing immune function, thereby promoting overall immune nutrition and restoring the body's balance.