A dual mechanism with H2S inhibition and membrane damage of morusin from Morus alba Linn. against MDR-MRSA.

It's urgent to discover new antibiotics along with the increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens. In the present investigation, morusin exhibited rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) by targeting the phospholipid of bacterial inner membrane, increasing membrane rigidity and disrupting bacterial homeostasis together with the membrane permeability, which caused fundamental metabolic disorders. Furthermore, morusin can also accumulate ROS, suppress H2S production, and aggravate oxidative damage in bacteria. Importantly, morusin also inhibited the spread of wounds and reduced the bacterial burden in the mouse model of skin infection caused by MRSA. It's a chance to meet the challenge of existing antibiotic resistance and avoid the development of bacterial resistance, given the multiple targets of morusin.

Formononetin Derivative for Osteoporosis by Simultaneous Regulating Osteoblast and Osteoclast.

Seven new formononetin derivatives (1-7) were designed and prepared from formononetin (phase II phytoestrogen). The derivatives 9-butyl-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (2) and 9-(furan-3-ylmethyl)-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (7) promoted significant osteoblast formation by modulating the BMP/Smad pathway. Compound 7 exhibited potent antiosteoclastogenesis activity in RANKL-induced RAW264.7 cells and ovariectomy (OVX)-induced osteoporosis in mice by regulation of the RANK/RANKL/OPG pathway. Compound 7 regulated osteoblast and osteoclast simultaneously and showed better effect than the well-known drug ipriflavone in vivo, suggesting 7 as a patented antiosteoporosis candidate.

A new therapeutic strategy for infectious diseases against intracellular multidrug-resistant bacteria.

Bacterial infections result in 7,700,000 deaths per year globally, with intracellular bacteria causing repeated and resistant infection. No drug is currently licenced for the treatment of intracellular bacteria. A new screening platform mimicking the host milieu has been established to explore phytochemical antibiotic adjuvants. Previously neglected isoprenylated flavonoids were found to be effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Specifically, the synergistic effect between glabrol and streptomycin against intracellular bacteria was observed for the first time. The glabrol-streptomycin combination targets bacterial inner membrane phospholipids, disrupts arginine biosynthesis, inhibits cell wall proteins and biofilm formation genes (agrA/B/C/D), and promotes ROS production, causing subsequent membrane and wall damage. To enhance the selective uptake of combination drug into infected cells, hyaluronic acid-streptomycin-lipoic acid-glabrol nanoparticles (HSLGS-S) were designed and synthesized to trigger the intracellular delivery of the glabrol-streptomycin combination. Thus, the treatment can be transported into the infected intracellular region and selectively release the glabrol-streptomycin combination to the bacterial at site. The bioactivity of HSLGS-S in clearing intracellular bacteria was 20-fold higher than that of the glabrol-streptomycin combination alone in vitro and 2- to 10-fold higher in vivo.

Structure optimizing of flavonoids against both MRSA and VRE.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) cause more than 100,000 deaths each year, which need efficient and non-resistant antibacterial agents. SAR analysis of 162 flavonoids from the plant in this paper suggested that lipophilic group at C-3 was crucial, and then 63 novel flavonoid derivatives were designed and total synthesized. Among them, the most promising K15 displayed potent bactericidal activity against clinically isolated MRSA and VRE (MICs = 0.25-1.00 µg/mL) with low toxicity and high membrane selectivity. Moreover, mechanism insights revealed that K15 avoided resistance by disrupting biofilm and targeting the membrane, while vancomycin caused 256 times resistance against MRSA, and ampicillin caused 16 times resistance against VRE by the same 20 generations inducing. K15 eliminated residual bacteria in mice skin MRSA-infected model (>99 %) and abdominal VRE-infected model (>92 %), which was superior to vancomycin and ampicillin.

New resorcylic acid derivatives of Lysimachia tengyuehensis against MRSA and VRE by interfering with bacterial metabolic imbalance.

The abuse of antibiotics leads to the rapid spread of bacterial resistance, which seriously threatens human life and health. Now, 8 resorcylic acid derivatives, including 4 new compounds (1-4) were isolated from Lysimachia tengyuehensis by bio-guided isolation, and they inhibited both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) (MIC = 4-8 µg/mL). Notably, 1 and 2 rapidly killed MRSA and VRE within 40 min without drug resistance in 20 days. Mechanically, they potently disrupted biofilm and cell membrane by interfering with bacterial metabolic imbalance. The structure-activity relationship (SAR) revealed that the lipophilic long carbon chains (C-5/C-6) and hydrophilic hydroxyl/carboxyl groups were essential for the anti-MRSA and VRE bioactivity. Additionally, they effectively recovered MRSA-infected skin wounds and VRE-infected peritoneal in vivo. Resorcylic acid derivatives showed significant anti-MRSA and VRE bioactivity in vitro and in vivo with potential application for the first time.