Plant derived phenolic acids can dramatically enhance the activity of existing antibiotics against multidrug resistant E. coli, offering a promising new tool in the global fight against antimicrobial resistance. In laboratory and insect models, these natural compounds helped an older antibiotic kill resistant bacteria more efficiently and reduced the chance that new resistance would emerge.
"Instead of waiting many years and spending enormous resources to develop brand new antibiotics, we show that small molecules already present in plants can breathe new life into the drugs we rely on today," said senior author Zeyou Chen of Nankai University in Tianjin, China. "Our findings suggest that something as simple as pairing the right plant compound with an existing drug could make a real difference for difficult infections."
Background: a stalled antibiotic pipeline
Antibiotic resistant infections are a growing threat to human and animal health worldwide, while the development of new antibiotics has slowed to a trickle in recent decades. Tetracycline, one of the earliest and most affordable antibiotics, remains widely used in livestock and continues to face high resistance rates in pathogens such as E. coli, particularly in regions like East Asia, the Pacific and sub Saharan Africa.
Because bringing a new antibiotic to market can take more than 10 years and cost over one billion US dollars, researchers are increasingly turning to "antibiotic adjuvants" molecules that restore or boost the effectiveness of existing drugs. Phenolic acids are small aromatic compounds that plants use as part of their defense against microbes and insects and are already known for their antioxidant and antimicrobial properties.
What the researchers did
The team tested 15 different phenolic acids, including salicylic, gallic, caffeic and gentisic acids, for their ability to work together with tetracycline against multidrug resistant E. coli strains isolated from the laboratory and from extraintestinal pathogenic infections. Using standard microdilution and checkerboard assays, they found that all 15 compounds showed clear synergy with tetracycline, meaning that much lower doses of the antibiotic were needed to halt bacterial growth.
Time kill experiments revealed that tetracycline or phenolic acids alone had limited impact on the resistant bacteria, but the combinations led to strong and sustained bacterial killing, sometimes accompanied by visible cell lysis. The researchers also observed that several phenolic acids could enhance the activity of another antibiotic, kanamycin, suggesting the approach might extend beyond a single drug.
How plant compounds boost antibiotic uptake
Mechanistic experiments showed that the phenolic acids make it easier for tetracycline to enter and stay inside bacterial cells. Using a fluorescent whole cell biosensor strain that glows in proportion to tetracycline uptake, the team demonstrated that all tested phenolic acids increased intracellular tetracycline in a dose dependent manner while simultaneously suppressing bacterial growth.
Further analysis indicated that these plant compounds impair key bacterial defenses. They reduced the expression and activity of major efflux pumps such as AcrB and TetA, which normally pump antibiotics out of the cell, and disrupted the proton motive force that fuels these pumps. Some phenolic acids also increased the permeability of the inner bacterial membrane, making it easier for tetracycline to reach its ribosomal target.
Tests in an infection model and resistance evolution
To move beyond petri dishes, the researchers turned to larvae of the wax moth Galleria mellonella, a widely used in vivo infection model. When the larvae were infected with a tetracycline resistant E. coli strain, treatment with tetracycline alone offered only limited protection, whereas combining tetracycline with selected phenolic acids such as gentisic acid significantly improved survival, with up to 80 percent of larvae alive after five days.
Importantly, long term evolution experiments with E. coli exposed to low doses of tetracycline showed that the antibiotic on its own quickly drove an eightfold increase in resistance over 30 days. In contrast, when tetracycline was paired with phenolic acids at similarly low doses, the bacteria failed to develop detectable resistance during the same period, hinting that such combinations could help slow the spread of resistance in real world settings.
Future applications and next steps
Because phenolic acids are abundant in many plant based foods and forages, the authors suggest that co administering selected phenolic acids with tetracycline in animal production could become a practical strategy to improve treatment outcomes and reduce resistance pressure. At the same time, they caution that issues such as stability, bioavailability, potential toxicity and the risk of new adaptive mechanisms in bacteria must be carefully evaluated before clinical or field use.
"Our work highlights plant phenolic acids as a rich and largely untapped source of antibiotic boosters," said co author Anping Peng. "With rational design and optimization, these natural scaffolds could be transformed into a new generation of safe and effective adjuvants to support the antibiotics we already have."
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Journal reference: Peng A, Yin L, Wang X, Yuan S, Wang M, et al. 2025. Plant phenolic acids enhance antibiotic efficacy against multidrug-resistant extraintestinal pathogenic Escherichia coli. Biocontaminant 1: e010
https://www.maxapress.com/article/doi/10.48130/biocontam-0025-0013
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Biocontaminant is a multidisciplinary platform dedicated to advancing fundamental and applied research on biological contaminants across diverse environments and systems. The journal serves as an innovative, efficient, and professional forum for global researchers to disseminate findings in this rapidly evolving field.
