The aminoglycoside-modifying enzyme Eis2 activates FF-NH2.
Scientists at St. Jude Children’s Research Hospital have developed a strategy that turns bacterial drug resistance mechanisms against the pathogen itself. By using a structurally modified form of the antibiotic florfenicol, the researchers were able to exploit resistance pathways in Mycobacterium abscessus, enhancing and sustaining the drug’s antibacterial effect. This approach offers a potentially safer and more effective treatment for infections caused by antibiotic-resistant bacteria.
Prolonged antibiotic therapy can cause mitochondrial toxicity, contributing to hearing loss and disruption of the healthy microbiome. However, inadequate treatment of Mycobacterium abscessus infections can be rapidly life-threatening, particularly in individuals with obstructive lung disease or compromised immune systems, including patients with hematological malignancies.
During the development of chloramphenicol analogs, researchers found that a modified florfenicol displayed potent activity against wild-type M. abscessus but was inactive in strains lacking WhiB7. Further analysis revealed that the drug functions as a prodrug, requiring activation within the bacterium. Eis2, a protein induced by WhiB7, converts the florfenicol analog into its active form. Activation of the drug inhibits the ribosome, further stimulating WhiB7, which generates more Eis2 and perpetually amplifies the antibiotic’s effect.
Image Credit: Nature Microbiology (2025). DOI: 10.1038/s41564-025-02147-9 (PhysOrg)
By St. Jude Children’s Research Hospital
