Researchers found that glucose availability drives resistance to the antibiotic fosfomycin in Enterobacter cloacae complex bacteria, Nature Communications reported on Sept. 3, 2026.
Heteroresistance occurs when a phenotypically unstable subpopulation of resistant cells coexists alongside a majority population of susceptible cells. In the peer-reviewed study, extracellular glucose triggered catabolite repression, which downregulated GlpT, a cellular transport protein that bacteria use to import glycerol and fosfomycin.
Single-cell variations in the expression of GlpT drove the emergence of the resistant subpopulation, combined with the expression of fosA acting as a resistance enhancer. Because environmental glucose alters glpT expression, resistant cells grew far more prevalent under high-glucose conditions.
Animal trials mirrored that metabolic response inside living hosts. In murine models of hyperglycemia and diabetes, the fosfomycin-resistant subpopulation appeared at higher frequencies during infection. The findings indicate that the metabolic context of an infection, including underlying disease conditions, directly affects bacterial resistance levels during medical treatment.
Co-lead authors Jacob E. Choby and David A. Hufnagel contributed equally to the study, working with Muqing Ma, Tugba Ozturk, Victor I. Band, Minsu Kim, and David S. Weiss at the Emory Antibiotic Resistance Center and the Emory Vaccine Center. Choby has since joined the Department of Microbiology and Immunology at the University of North Carolina School of Medicine.
Funding came from the National Institutes of Health, the Burroughs Wellcome Fund, and the Cystic Fibrosis Foundation. The team received bacterial isolates from the CDC-funded Multi-Site Gram-negative Surveillance Initiative, the Georgia Emerging Infections Program, and Brian Conlon of the University of North Carolina at Chapel Hill.
