Inhalable self-assembled celastrol for acute bacterial pneumonia treatment

A team led by Prof. Jing Liu from the National Center for Nanoscience and Technology has conducted a study on "Inhalable Self-Assembled Celastrol for Acute Bacterial Pneumonia Treatment". They developed inhalable chitosan-coated self-assembled celastrol nanoparticles (CSC NPs) to address the problem of acute bacterial pneumonia caused by Staphylococcus aureus (SA) and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA).

MRSA is a well-recognized cause of bacterial pneumonia, leading to increased morbidity and mortality worldwide. However, rediscovering antibacterial compounds from established antibiotic classes is a bottleneck, and there is a risk of superbugs emergence and microbiome imbalance. Using non-antibiotics has a potential advantage: they do not impose "life or death" selection pressure on bacteria, making it less likely for bacteria to evolve resistance. Thus, the team used the Chinese herbal compound celastrol (CST), a triterpene methylene quinone, to synthesize CSC NPs.

The CSC NPs are designed for nebulization with an aerodynamic size of 3 μm, allowing predominant deposition in the deep lung. They achieve high drug loading efficiency through hydrophobic interaction and enhanced mucoadhesive properties via electrostatic interactions with the mucus layer, resulting in prolonged pulmonary retention. Then, they undergo acid-responsive degradation at bacterial infection sites, facilitating mucus penetration.

Further mechanistic analysis shows that CSC NPs act as a non-competitive inhibitor of dehydrosqualene synthase (CrtM), reducing staphyloxanthin (STX)-a significantly important virulence factor in S. aureus. This disrupts the bacterial membrane and enhances immune clearance by host macrophages and neutrophils. In vitro experiments demonstrated that CSC NPs effectively inhibit SA and MRSA growth with a minimum inhibitory concentration (MIC) of 8 μg/mL, achieving nearly 100% and 99% antibacterial rates respectively. They also showed strong antibiofilm activity and low resistance development. In vivo tests in mouse models confirmed the therapeutic potential. Nebulized CSC NPs significantly reduced lung bacterial burden, with antibacterial rates of 97% (SA) and 94% (MRSA).

"This study provides a new alternative strategy by using conventional natural products to overcome SA and MRSA infections with great prospects for clinical translation” said corresponding author Prof. Jing Liu. "We hope the general applicability of adhesive polymer-coated self-assembled small molecules for aerosolized administration will also be expanded in other models (e.g. COVID-19 and fungal infection). Furthermore, based on the excellent antibacterial effect via staphyloxanthin reduction induced bacterial membrane disruption and immune clearance, we have faith in non-antibiotics molecules that blocking bacterial virulence factors will be the development trend of antimicrobial infection drugs in the future."

This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Beijing Nova Program, the Taishan Scholars Program of Shandong Province, and the Hundred-Talent Program of the Chinese Academy of Sciences.

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