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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Parasitic Diseases Laboratory » Research » Publications at this Location » Publication #415311
Research Project: Molecular, Immune and Microbiome Approaches for Mitigating GI Nematode Infections of Livestock

Location: Animal Parasitic Diseases Laboratory

Title: Exploiting strong synergies between punicalagin and cefoperazone to combat methicillin-resistant Staphylococcus aureus infections

Author
item LIU, F. - Zhengzhou University
item REN, J. - Zhengzhou University
item ZHANG, P. - Zhengzhou University
item SUN, W. - Zhengzhou University
item Smith, Allen
item Li, Robert
item YANG, H. - Zhengzhou University

Submitted to: npj Biofilms and Microbiomes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/26/2025
Publication Date: 10/8/2025
Citation: Liu, F., Ren, J., Zhang, P., Sun, W., Smith, A.D., Li, R.W., Yang, H.Y. 2025. Exploiting strong synergies between punicalagin and cefoperazone to combat methicillin-resistant Staphylococcus aureus infections. npj Biofilms and Microbiomes. 11. Article e193. https://doi.org/10.1038/s41522-025-00822-7.
DOI: https://doi.org/10.1038/s41522-025-00822-7

Interpretive Summary: Methicillin-resistant Staphylococcus aureus (MRSA) is widespread in nature. Farm animals, such as pigs, cattle and poultry, are frequently colonized with MRSA, posing a severe threat to human health via their zoonotic transmission to humans by direct animal contact, environmental contamination, or livestock products. In this study, we identified a natural product, punicalagin (PA), that possesses potent antimicrobial activities by target screening of a key virulence factor crucial to bacterial attachment. Strong synergism between PA and an existing antibiotic led to a 99% reduction in bacterial load in major murine organs and completely protected mice infected by MRSA. Our findings demonstrate that as a natural product with a highly desired safety and bioavailability profile, PA presents a promising alternative to antimicrobial for its potent prophylactic and curative effects and can play an important role in mitigating antibiotic drug resistance.

Technical Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious public health threat. The effectiveness of existing antibiotics to treat MRSA infections is diminishing. This study aims to develop novel antimicrobial alternatives to fight MRSA infections. We conducted an anti-virulence screening targeting the L-lectin module (SLL) of the S. aureus cell wall protein serine-rich adhesin for platelets (SraP) against a database consisting of >14,000 natural products. The top candidates identified, including the polyphenol punicalagin (PA), were validated using surface plasmon resonance and a range of microbiological assays, including cell adhesion and invasion, biofilm formation, checkboard assays, microbiome studies, and RNAseq, for their properties to combat MRSA. The efficacy of punicalagin in treating MRSA infections, alone or in combination with existing antibiotics, was investigated using mouse models. PA was bound to the virulence factor SraP with high affinity and was highly effective in inhibiting MRSA colonization. PA significantly reduced the expression of multiple genes associated with ß-lactam resistance and disrupted biofilm formation. The synergistic effects between PA and cefoperazone (CF), a well-known bactericidal, were remarkable. The combination of PA and CF reduced the bacterial load in key murine organs by >98.9% and completely protected mice infected by MRSA. PA restored native gut microbiota disrupted by antibiotics, enriched butyrate-producing species, and repressed tissue inflammation. PA acted as a potent anti-virulence agent in addition to its intrinsic anti-inflammatory properties. Taking advantage of the strong synergism between PA and CF represents a promising strategy for combating MRSA infection and antibiotic resistance.