Metals play essential roles in life
by coordination with small
molecules, proteins, and nucleic acids. Although the coordination
of copper ions in many proteins and methanobactins is known, the coordination
chemistry of Cu(II) in natural products and their biological functions
remain underexplored. Herein, we report the discovery of a Cu(II)-binding
natural product, chalkophomycin (CHM, 1), from Streptomyces sp. CB00271, featuring an asymmetric square-coordination
system of a bidentate diazeniumdiolate and a conjugated 1H-pyrrole 1-oxide-oxazoline. The structure of 1 may inspire
the synthesis of Cu(II) chelators against neurodegenerative diseases
or Cu(II)-based antitumor therapeutics.
Serious
bacterial infections by multi-drug-resistant pathogens
lead to human losses and endanger public health. The discovery of
antibiotics with new modes of action, in combination with nanotechnology,
might offer a promising route to combat multi-drug-resistant pathogens.
Platensimycin (PTM), a potent inhibitor of FabB/FabF for bacterial
fatty acid biosynthesis, is a promising drug lead against many drug-resistant
bacteria. However, the clinical development of PTM is hampered by
its poor pharmacokinetics. Herein, we report a nanostrategy that encapsulated
PTM in two types of nanoparticles (NPs) poly(lactic-co-glycolic acid) (PLGA) and poly(amidoamine) (PAMAM) dendrimer to
enhance its antibacterial activity in vitro and in vivo. The PTM-encapsulated NPs were effective to inhibit Staphylococcus aureus biofilm formation, and killed more S. aureus in a macrophage cell infection model over free
PTM. The pharmacokinetic studies showed that PTM-loaded PLGA and PAMAM
NPs exhibited increased AUC0‑t (area under the curve)
(∼4- and 2-fold) over free PTM. In a mouse peritonitis model,
treatment of methicillin-resistant S. aureus infected
mice using both PTM-loaded NPs (10 mg/kg) by intraperitoneal injection
led to their full survival, while all infected mice died when treated
by free PTM (10 mg/kg). These results not only suggest that PTM-loaded
NPs may hold great potential to improve the poor pharmacokinetic properties
of PTM, but support the rationale to develop bacterial fatty acid
synthase inhibitors as promising antibiotics against drug-resistant
pathogens.
To increase the efficacy of small molecule chemotherapeutic drug (SMCD) and reduce its toxic and side effects, we selected two model drugs doxorubicin (DOX) and chloroquine (CQ). DOX is a SMCD and CQis a chemosensitizer with autophagy inhibition. Poly(lactic-co-glycolic acid) (PLGA) and alpha-tocopherol polyethylene glycol 1000 succinate were chosen as delivery carriers to design and prepare a novel type of drug co-delivery single-nanoparticles by emulsification-solvent volatilisation, named NP DOX+CQ . The physicochemical properties of NP DOX+CQ were characterised. Then A549 cells and A549/Taxol cells were used for the in vitro anti-cancer effect study. At the same time, cellular uptake, intracellular migration and anti-cancer mechanism of nanoparticles were studied. The NPs showed a uniform spherical shape with good dispersibility, and both drugs had good encapsulation efficiency and loading capacity. In all formulations, NP DOX+CQ showed the highest in vitro cytotoxicity. The results showed that NPs could protect drugs from being recognised and excluded by P-glycoprotein (P-gp). Moreover, the results of the mechanistic study demonstrated that NPs were transported by autophagy process after being taken up by the cells. Therefore, during the migration of NP DOX+CQ , CQ could exert its efficacy and block autophagy so that DOX would not be hit by autophagy. Western Blot results showed that NP DOX+CQ had the best inhibition effect of autophagy. It can be concluded that the system can prevent the drug from being recognised and excluded by P-gp, and CQ blocks the process of autophagy so that the DOX is protected and more distributed to the nucleus of multidrug resistance (MDR) cell. The NP DOX+CQ constructed in this study provides a feasible strategy for reversing MDR in tumour cells.
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