New Study Reveals Bacteria's Metabolic Weakness When Exposed to Penicillin

Researchers find combining penicillin with a drug that blocks nucleotide production can eradicate antibiotic-tolerant bacteria

Mar. 13, 2026 at 3:39am

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A new study led by researchers at Cornell University has uncovered a surprising metabolic weakness in bacteria that become tolerant to the antibiotic penicillin. The study found that under penicillin stress, bacteria become starved for nucleotides, the essential molecular building blocks needed for cell processes. By combining penicillin with a drug that further blocks nucleotide production, the researchers were able to reduce survival of antibiotic-tolerant bacteria by more than 100,000-fold, pointing to a potential new treatment strategy to combat antibiotic resistance.

Why it matters

Antibiotic tolerance is a concerning precursor to full-blown antibiotic resistance, allowing bacteria to survive high doses of drugs like penicillin. This study provides important insights into the metabolic changes that enable this tolerance, revealing a vulnerability that could be exploited to make existing antibiotics more effective against hard-to-kill bacteria.

The details

The study, published in npj Antimicrobials & Resistance, focused on the cholera-causing bacterium Vibrio cholerae. Researchers found that under penicillin stress, the bacteria stop dividing but remain metabolically active, allowing them to survive until the antibiotic fades. By analyzing gene expression and metabolite levels, the team discovered that penicillin causes a sharp drop in nucleotides, the essential building blocks for DNA and other cell components. This nucleotide shortage appears to be a critical weakness, as treating the bacteria with penicillin plus a drug that further interferes with nucleotide production resulted in over 100,000-fold reduction in survival, even in other antibiotic-resistant bacteria like Klebsiella pneumoniae and E. coli.

  • The study was published on March 13, 2026.

The players

Megan Keller

A postdoctoral researcher who led the study.

Tobias Dörr

An associate professor of microbiology in the College of Agriculture and Life Sciences and faculty in the Weill Institute for Cell and Molecular Biology, who was the senior author on the study.

Vibrio cholerae

The bacterium that causes cholera, which was used in the study to investigate antibiotic tolerance.

Klebsiella pneumoniae

A bacterium that causes antibiotic-resistant pneumonia and urinary tract infections, which was also tested in the study.

E. coli

A food-borne pathogen that was also tested in the study.

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What they’re saying

“When exposed to penicillin the bacteria stop dividing while the drug is present, but they stay metabolically active and survive. Once the antibiotic fades, they can return to normal growth and continue infection.”

— Tobias Dörr, Associate professor of microbiology

“The most striking change our research revealed, though, was a sharp drop in nucleotides, the critical precursors for DNA and other important cell components.”

— Tobias Dörr, Associate professor of microbiology

“Either drug alone eradicated only modest numbers of bacteria, but together they reduced V. cholerae survival by more than 100,000-fold.”

— Tobias Dörr, Associate professor of microbiology

What’s next

The researchers plan to further investigate the potential of combining penicillin with drugs that target nucleotide production as a new therapeutic approach to combat antibiotic-tolerant bacteria.

The takeaway

This study uncovers a critical metabolic vulnerability in bacteria that become tolerant to penicillin, pointing to a promising new strategy to make existing antibiotics more effective against hard-to-kill, antibiotic-resistant pathogens.