2026/06/10 by Aaron C. Nolan, J. Kelly, Jongsam Ahn +4 · 1 voice
Medicine · Biochemistry, Genetics and Molecular Biology · #Pneumocystis jirovecii pneumonia detection and treatment #Biochemical and Molecular Research #HIV/AIDS drug development and treatment
paper · doi:10.1128/aac.00377-26
ABSTRACT Efforts to improve the effectiveness of existing interventions for antimicrobial-resistant infections include identifying new ways to overcome resistance to licensed antibiotics using adjuvants or deploying antibiotics in novel combinations. Although antibiotics targeting the bacterial cell wall (e.g., β-lactams) and folate metabolism (e.g., trimethoprim-sulfamethoxazole [TMP-SMX]) remain cornerstones of modern healthcare, resistance to both classes poses an ongoing therapeutic challenge. We recently demonstrated that purine nucleosides can act as potent antibiotic adjuvants, restoring β-lactam susceptibility in methicillin-resistant Staphylococcus aureus (MRSA). Here, we show that guanosine significantly reduces intracellular thymidine levels in MRSA and potentiates the activity of antifolate antibiotics (TMP-SMX), as well as the pyrimidine antimetabolites 5-fluorouracil and 5-fluorouridine. Incorporation of oxacillin into guanosine-antifolate or guanosine-pyrimidine analog combinations further enhanced killing of both planktonic and biofilm-associated MRSA. Thymidine depletion was accompanied by elevated intracellular reactive oxygen species and dissipation of membrane potential, providing mechanistic insight into the bactericidal effects of these combinations. Together, these findings demonstrate that guanosine expands MRSA susceptibility beyond β-lactams to include additional clinically relevant antimicrobial drug classes commonly used to treat bacterial infections.