Adrián González-López completes PhD on the structural mechanisms behind fusidic acid resistance
Adrián López González defending his thesis
Adrián González-López, PhD student at Uppsala Antibiotic Center, defended his thesis Structural mechanisms of fusidic acid inhibition and resistance on 27 May 2026 at Uppsala University. Adrián is the seventh member of UAC's second cohort to defend.
How fusidic acid stops bacterial growth
Fusidic acid (FA) is an antibiotic used to treat Staphylococcus aureus infections. It works by trapping elongation factor G (EF-G) on the ribosome, which is the molecular machine bacteria use to produce proteins. With EF-G stuck, protein synthesis stalls and bacteria cannot grow. Resistance to FA in S. aureus arises through three main mechanisms, the most clinically widespread of which involves a protein called FusB that releases EF-G from the ribosome even when FA is still bound. How FusB achieves this had remained unresolved. Adrián's thesis addresses that question directly.
Visualizing inhibition and resistance at atomic resolution
The first two papers on Adrian’s thesis used high-resolution cryo-EM to map FA inhibition and resistance in S. aureus. Paper I determined the first structures of S. aureus EF-G trapped on the ribosome by FA and an FA analogue, clarifying how known resistance mutations affect the drug's binding environment and providing a structural foundation for designing improved FA derivatives.
Paper II solved the mechanism of FusB-type resistance. Using a time-resolved cryo-EM approach developed in-house using on-grid mixing to capture a transient rescue complex, Adrián showed that FusB forces EF-G into a non-canonical conformation that reduces its contact with the ribosome by approximately 30%, triggering release even though FA remains bound. This is the first confirmed example of a type III target protection mechanism: restoring the inhibited function of the drug's target without removing the drug. An unexpected finding was that FusB also binds directly to the ribosome independently of EF-G, suggesting functions that may extend beyond antibiotic resistance.
Resistance beyond S. aureus, and new insights into ribosome recycling
Paper III characterised a FA resistance operon in Streptomyces canus encoding three components: a FusB homologue that likely rescues EF-G, an esterase that enzymatically deactivates FA, and a transcriptional regulator that senses FA and switches the operon on in response. Together they form a coordinated, inducible resistance system combining two complementary mechanisms.
Paper IV used FA to trap and visualize ribosome recycling in S. aureus, known to be the final step of protein synthesis, in which the ribosome disassembles after translation ends. The structures reveal how EF-G and ribosome recycling factor cooperate to disrupt intersubunit contacts and split the ribosome, and show that FA predominantly inhibits this process by locking EF-G alone on the ribosome before the recycling factor can bind.
A structural basis for next-generation antibiotic development
Adrián's thesis provides the most detailed structural picture to date of FA inhibition, FA resistance, and ribosome recycling in a clinically relevant pathogen. The work offers a concrete foundation for structure-guided development of improved antibiotics and resistance inhibitors.
UAC congratulates Adrián on an outstanding contribution to antibiotic resistance research.
