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

Honokiol targets HptA to block G‑6‑P uptake and induce lethal carbon starvation. • Carbon starvation collapses MRSA central metabolism and weakens biofilm formation. • Metabolic inhibition lowers NADPH, amplifies ROS, and drives oxidative damage. • Honokiol reduces MRSA burden, dampens TLR2/NF‑ κ B, and accelerates wound healing. • HptA is absent in mammals, giving HNK high target selectivity and low toxicity. 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- κ B 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‑ κ B signaling, accelerating wound healing through a localized antibacterial action. Download: Download high-res image (358KB) Download: Download full-size image