Researchers have identified a weakness in antibiotic-resistant bacteria that could help restore susceptibility to existing treatments by disrupting a lipid carrier essential for bacterial cell-wall synthesis.
Researchers at Umeå University in Sweden have identified a vulnerability in antibiotic-resistant bacteria that could provide a new strategy for restoring susceptibility to existing treatments.
The study, published in Nature Communications, found that disrupting the availability of undecaprenyl phosphate, a lipid molecule essential for bacterial cell-wall synthesis, could make resistant bacteria more vulnerable to β-lactam antibiotics, including penicillins.
The findings could support the development of combination therapies designed to overcome antibiotic resistance.
Disrupting bacterial cell-wall synthesis
β-lactam antibiotics work by interfering with bacterial cell-wall synthesis. However, resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) have evolved mechanisms that allow them to continue building their cell walls despite treatment.
To understand how resistance develops, researchers investigated genetic changes in MRSA following antibiotic exposure. Although these adaptations enabled the bacteria to regain resistance, they also introduced a weakness linked to undecaprenyl phosphate, a lipid carrier responsible for transporting the building blocks needed for cell-wall synthesis.
Reducing the availability of this lipid carrier disrupted cell-wall production, making resistant bacteria more vulnerable to antibiotic treatment. To investigate this effect further, the team used simvastatin, a cholesterol-lowering drug that can interfere with bacterial lipid metabolism. Simvastatin-induced depletion of undecaprenyl phosphate exposed vulnerabilities associated with certain resistance mutations, suggesting a potential way to restore antibiotic susceptibility.
Exploiting resistance mechanisms
The researchers observed that some genetic adaptations that helped bacteria survive antibiotic treatment also reduced their growth and ability to cause infection.
“What surprised us was that some mutations that help bacteria survive antibiotic treatment simultaneously create new vulnerabilities. Rather than becoming stronger in every respect, the bacteria appear to be forced into a trade-off,” said Gabriel Torrens, first author of the study.
Similar vulnerabilities were identified in Streptococcus pneumoniae, suggesting that the mechanism may be relevant to other antibiotic-resistant Gram-positive bacteria.
What surprised us was that some mutations that help bacteria survive antibiotic treatment simultaneously create new vulnerabilities.
The findings suggest that weaknesses created by antibiotic resistance mechanisms could be exploited to restore the effectiveness of existing treatments, rather than relying solely on developing new antibiotics.
Although further research is needed to determine whether this strategy can be used safely and effectively in patients, it could support the development of antibiotic adjuvants that improve the activity of existing drugs.
A patent application has already been filed based on the findings.
Reference
Torrens G, et al. Statin-induced lipid carrier stress reveals a conserved vulnerability in β-lactam-resistant Gram-positive bacteria. Nat Commun. 2026;17:6680. doi:10.1038/s41467-026-75729-8.
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