Cancer cells rely on lipogenesis in addition to exogenous lipid uptake, and fatty acid synthase (FASN) is aberrantly overexpressed in myeloid leukemia, yet its role in leukemogenesis is unclear. We show that FASN is essential for leukemogenesis. Its genetic ablation impairs leukemic cell growth, survival, and clonogenicity in vitro, and reduces disease burden in vivo, without significantly affecting normal hematopoiesis. We further identify a platensimycin derivative compound MS-C19 as a potent FASN inhibitor. MS-C19 suppresses growth and clonogenicity in clinical acute myeloid leukemia (AML) samples. Mechanistically, FASN inhibition or deficiency activates lysosomal and inflammatory gene programs, inducing lysosomal membrane permeabilization and associated cell death but not lysosome biogenesis. We further identify that GRN, a lysosomal and neuroinflammatory gene, is potently transcribed by TFEB upon FASN inhibition. GRN depletion reverses the anti-leukemic effects of FASN loss. Our findings establish FASN as a therapeutic target and support its pharmacological inhibition by MS-C19 for leukemia treatment.

Bacterial wilt, caused by the soil-borne phytopathogen Ralstonia solanacearum (R. solanacearum), poses a serious threat to global agriculture. In this study, 26 actinomycete strains were isolated from the rhizosphere of traditional Chinese medicinal plants. Among them, Streptomyces sp. JL2001 exhibited strong inhibitory activity against R. solanacearum both in vitro and in planta. UPLC-QTOF-MS/MS analysis identified aerugine as the major active compound, alongside five structurally related 2-hydroxyphenylthiazoline derivatives. Chemically synthesized aerugine showed broad-spectrum antibacterial activity, significantly inhibiting planktonic growth and biofilm formation and alleviating bacterial wilt symptoms in tomato seedlings under hydroponic and soil-based conditions. Mechanistically, aerugine disrupts bacterial membranes, interferes with lipid metabolism, and downregulates key virulence systems, including flagellar assembly and the type III secretion system. These findings were supported by electron microscopy, proteomic profiling, and qPCR validation. Whole-genome sequencing of JL2001 revealed a 7.75 Mb chromosome containing 22 biosynthetic gene clusters (BGCs), including a thiazostatin-like NRPS-dependent BGC likely responsible for aerugine biosynthesis. Importantly, soilbased assays demonstrated that aerugine significantly and dose-dependently suppressed R. solanacearum in natural soil, while also inducing changes in microbial composition. Later-stage increases in bacterial abundance and diversity, particularly of morphologically distinct non-pathogenic colonies, suggest that aerugine not only eliminates pathogens but may also promote beneficial microbiota -a dual protection mechanism. This study highlights Streptomyces sp. JL2001 and aerugine as promising agents for the sustainable control of bacterial wilt and provides new insights into their molecular antibacterial mechanisms.

Cancer cells rely on lipogenesis in addition to the exogenous lipid up-taking, in which the lipogenic enzyme fatty acid synthase has aberrant over-expression in various cancers, including myeloid leukemia. However, the precise role of FASN in the leukemogenesis remains elucidative. Here, by genetic manipulation of FASN in vitro and in vivo, we demonstrated that FASN was essential for leukemogenesis. Ablation of FASN either by RNA interference or CRISPR-Cas9 knockout impeded the leukemic cell growth, survival, clonogenicity in vitro and leukemic burden in vivo. The absence of FASN minimally affected normal hematopoiesis but significantly attenuated or delayed leukemic progression in the oncogenic MLL-AF9 leukemia mouse model, leading to prolonged animal survival. By screening a library of platensimycin derivatives, we identified compound MS-C19 as a potent FASN inhibitor, which is superior to Orlistat or TVB-3166. Pharmaceutical targeting FASN by MS-C19 suppressed leukemic cell growth, clonogenicity and cell survival and induced myeloid differentiation in both leukemia cell lines and clinical AML blasts. Mechanistically, both MS-C19 insult and FASN deficiency triggered the activation of lysosomal and inflammatory gene expression. Depletion of Progranulin, a lysosomal and neuroinflammatory gene, in the presence of FASN depletion, significantly reverted the inhibition of leukemic cell growth, survival, and clonogenicity caused by FASN knockdown. Thus, mammalian FASN could be a therapeutic target for myeloid leukemia, and inhibition of FASN by the lead compound MS-C19 provides a promising approach for leukemia intervention.

mDia formin proteins regulate the dynamics and organization of the cytoskeleton through their linear actin nucleation and polymerization activities. We previously showed that mDia1 deficiency leads to aberrant innate immune activation and induces myelodysplasia in a mouse model, and mDia2 regulates enucleation and cytokinesis of erythroblasts and the engraftment of hematopoietic stem and progenitor cells (HSPCs). However, whether and how mDia formins interplay and regulate hematopoiesis under physiological and stress conditions remains unknown. Here, we found that both mDia1 and mDia2 are required for HSPC regeneration under stress, such as serial plating, aging, and reconstitution after myeloid ablation. We showed that mDia1 and mDia2 form hetero-oligomers through the interactions between mDia1 GBD-DID and mDia2 DAD domains. Double knockout of mDia1 and mDia2 in hematopoietic cells synergistically impaired the filamentous actin network and serum response factor-involved transcriptional signaling, which led to declined HSPCs, severe anemia, and significant mortality in neonates and newborn mice. Our data demonstrate the potential roles of mDia hetero-oligomerization and their non-rodent functions in the regulation of HSPCs activity and orchestration of hematopoiesis.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.

Platensimycin (PTM) is a promising natural product drug lead against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), while the clinical development was hampered by problems related to its poor solubility and pharmacokinetic properties. In this study, we used liposomes and micelles as carriers of PTM to prepare PTM nanoformulations for the treatment of MRSA infection in mice. PTM-loaded nanoparticles could effectively reduce residual bacteria in the MRSA-infected macrophage cell model, comparing to free PTM. More importantly, in vivo studies showed that encapsulation of PTM by liposomes or micelles effectively improved the pharmacokinetic properties of PTM in Sprague-Dawley rats and the survival rate of MRSA-infected C57BL/6J mice. Our study has thus suggested that the clinically used nanocarriers, such as liposome and micelle, might also be useful to improve the efficacy of other natural product drug leads to accelerate their in vivo evaluation and preclinical development.

The site- and diastereoselective functionalization of 40-OH in rapamycin by 3-hydroxyoxindole moieties was efficiently achieved through the active protic oxonium ylide trapping reactions using isatins, resulting in 31 new analogues of rapamycin. This study not only significantly expanded the known active rapalogs, but showcased the broad utility of multi-component reactions in late-stage functionalization of complex natural products.

Obesity is one of the major public health problems worldwide, mainly resulting from unhealthy lifestyles and diet. Gut microbiota dysbiosis may lead to obese humans and animals. Modulating gut bacteria through probiotics or certain dietary supplements could normalize gut microbiota and subsequently alleviate obesity. The daily consumption of Fuzhuan brick tea (FBT) or its extracts has been observed to alleviate obesity in humans and experimental animals. In this study, high-fat diet (HFD)-induced obesity in mice, such as body weight gain and fat accumulation, was prevented by the consumption of Eurotium cristatum, the dominant fungus during the manufacturing and storage of FBT. The dysbiosis of gut microbiota in C57BL/6J mice was also partially normalized. E. cristatum was able to modulate both gut fungal and bacterial compositions, based on the analysis of the microbiota composition of mice fecal samples (n = 5). E. cristatum increased acetate and butyrate-producing bacteria in mouse gut. There was five times more butyrate in the fecal samples from mice fed with E. cristatum than that from untreated HFD mice. Our results suggest that E. cristatum may be used as a probiotic fungus to alleviate obesity and to modulate gut microbiota in humans beneficially.

Staphylococcus aureus is one of the most common pathogens causing hospital-acquired and community-acquired infections. Methicillin-resistant S. aureus (MRSA)-formed biofilms in wounds are difficult to treat with conventional antibiotics. By targeting FabB/FabF of bacterial fatty acid synthases, platensimycin (PTM) was discovered to act as a promising natural antibiotic against MRSA infections. In this study, PTM and its previously synthesized sulfur-Michael derivative PTM-2t could reduce over 95% biofilm formation by S. aureus ATCC 29213 when used at 2 μg/mL in vitro. Topical application of ointments containing PTM or PTM-2t (2 × 4 mg/day/mouse) was successfully used to treat MRSA infections in a BABL/c mouse burn wound model. As a potential prodrug lead, PTM-2t showed improved in vivo efficacy in a mouse peritonitis model compared with PTM. Our study suggests that PTM and its analogue may be used topically or locally to treat bacterial infections. In addition, the use of prodrug strategies might be instrumental to improve the poor pharmacokinetic properties of PTM.

Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (1), followed by various C-C cross-coupling reactions in high yields. Antibacterial screening of these compounds in vitro yielded multiple hits with improved anti- Staphylococcus activities over PTM. Among them, compounds A1, A3, A17, and A28 exhibited improved antibacterial activities over PTM against methicillin-resistant Staphylococcus aureus (MRSA) in a mouse peritonitis model. Compound A28 was further shown to be effective against MRSA infection in a mouse wound model, in comparison to mupirocin. Therefore, the facile preparation and screening of these PTM derivatives, together with their potent antibacterial activities in vivo, suggest a promising strategy to improve the antibacterial activity and pharmacokinetic properties of PTM.

Three natural products of nonaketide biosynthetic origin, probably biosynthesized from nine molecules of malonyl-CoA, have been isolated. Herein we described the isolation and structure elucidation of huanglongmycin (HLM) A-C and identification of the putative hlm biosynthetic gene cluster from Streptomyces sp. CB09001, isolated from a karstic cave in Xiangxi, China. Albeit previously isolated, HLM A was reported for the first time to exhibit moderate cytotoxicity against A549 lung cancer cell line (IC50 = 13.8 ± 1.5 μM) and weak antibacterial activity against gram-negative clinical isolates. A putative biosynthetic pathway for HLM A, featuring a nonaketide-specific type II polyketide synthase, was proposed. It would be consistent with the isolation of HLM B and C, which are two new natural products and likely shunt metabolites during HLM A biosynthesis.

Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C. Compared to PTM, 6-pyrenyl PTM (6t) showed improved antibacterial activity against MRSA in a mouse peritonitis model. Our results support the strategy to target the essential fatty acid synthases in major pathogens, in order to discover and develop new generations of antibiotics.