The emergence and rapid spread of methicillin‐resistant Staphylococcus aureus (MRSA) raise a critical need for alternative therapeutic options. New antibacterial drugs and targets are required to combat MRSA‐associated infections. Based on this study, celastrol, a natural product from the roots of Tripterygium wilfordii Hook. f., effectively combats MRSA in vitro and in vivo. Multi‐omics analysis suggests that the molecular mechanism of action of celastrol may be related to Δ1‐pyrroline‐5‐carboxylate dehydrogenase (P5CDH). By comparing the properties of wild‐type and rocA‐deficient MRSA strains, it is demonstrated that P5CDH, the second enzyme of the proline catabolism pathway, is a tentative new target for antibacterial agents. Using molecular docking, bio‐layer interferometry, and enzyme activity assays, it is confirmed that celastrol can affect the function of P5CDH. Furthermore, it is found through site‐directed protein mutagenesis that the Lys205 and Glu208 residues are key for celastrol binding to P5CDH. Finally, mechanistic studies show that celastrol induces oxidative stress and inhibits DNA synthesis by binding to P5CDH. The findings of this study indicate that celastrol is a promising lead compound and validate P5CDH as a potential target for the development of novel drugs against MRSA.
The emergence of antimicrobial resistance is a global challenge. However, new drug development efforts consume considerable resources and time, and alleviating the pressure on existing drugs is the focus of our work.
Due to the large amount of antibiotics used for human
therapy,
agriculture, and even aquaculture, the emergence of multidrug-resistant Streptococcus suis (S. suis) led to serious public health threats. Antibiotic-assisted strategies
have emerged as a promising approach to alleviate this crisis. Here,
the polyphenolic compound gallic acid was found to enhance sulfonamides
against multidrug-resistant S. suis. Mechanistic analysis revealed that gallic acid effectively disrupts
the integrity and function of the cytoplasmic membrane by dissipating
the proton motive force of bacteria. Moreover, we found that gallic
acid regulates the expression of dihydrofolate reductase, which in
turn inhibits tetrahydrofolate synthesis. As a result of polypharmacology,
gallic acid can fully restore sulfadiazine sodium activity in the
animal infection model without any drug resistances. Our findings
provide an insightful view into the threats of antibiotic resistance.
It could become a promising strategy to resolve this crisis.
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