Targeting hexose phosphate transport regulatory protein A with the herbal-small molecule honokiol induces carbon starvation under nutrient stress to combat methicillin-resistant Staphylococcus aureus infection.

BACKGROUND

Methicillin-resistant Staphylococcus aureus (MRSA) compromises chronic wound healing, and growing antibiotic resistance necessitates novel agents that target unconventional bacterial vulnerabilities.

PURPOSE: To investigate the anti-MRSA efficacy of honokiol and to characterize hexose phosphate transport regulatory protein A (HptA), a regulator of alternative carbon source uptake under nutritional stress, as a therapeutic target.

METHODS

Anti-MRSA activity was evaluated in vitro, with MIC determination. HptA protein was purified, and HptA-honokiol interactions were characterized using molecular docking, bio-layer interferometry, and related techniques. Multi-omics analysis were performed to elucidate metabolic responses. Therapeutic efficacy was assessed in mouse model of MRSA-induced wound infection.

RESULTS

Honokiol exhibited moderate anti-MRSA activity with an MIC of 36 µg/ml. Mechanistically, honokiol allosterically locks HptA into a nonfunctional conformation, blocking glucose-6-phosphate uptake under nutrient-limited wound conditions. This induces carbon starvation, redox imbalance, and a ROS burst, leading to membrane damage, DNA fragmentation, and biofilm eradication. Local bacterial clearance subsequently reduced peptidoglycan-driven TLR2/NF-κB activation, attenuated inflammation, and significantly accelerated wound healing in vivo.

CONCLUSION

HptA is identified as a potential antibacterial target against MRSA. By blocking alternative carbon uptake, honokiol induces carbon starvation‑driven lethal stress; lowered bacterial burden then inhibits TLR2/NF‑κB signaling, accelerating wound healing through a localized antibacterial action.