Dihydro-α-Pyrone Antibiotics from a Soil-Derived Fungus <i>Talaromyces</i> sp. G23

Nine novel dihydro-α-pyrone derivatives, talaromypyrones A-I (<b>1</b>-<b>9</b>), were isolated from the soil-derived fungus <i>Talaromyces</i> sp. G23. These compounds share a conserved 3'<i>R</i>-configuration within the 4-hydroxy-5,6-dihydro-2-pyrone core but display notable variations in their flanking polyketide chains. Talaromypyrones A-H (<b>1</b>-<b>8</b>) demonstrate potent antibacterial activity against Gram-positive bacteria, including drug-resistant strains, while exhibiting excellent safety profile by showing no cytotoxicity toward normal human LO2 cells. However, they exhibit no activity against Gram-negative bacteria (likely due to their inability to penetrate the outer membrane) and fungi. Such antimicrobial profile, combined with the structural similarity to the α-pyrone antibiotic myxopyronin, suggests a potential target in the switch region of bacterial RNA polymerase (RNAP). Molecular docking studies revealed that talaromypyrone E (<b>5</b>) binds to the same site of RNAP as myxopyronin and forms additional hydrogen bonds between the 4-hydroxy-5,6-dihydro-2-pyrone core and the RNAP residues. Furthermore, talaromypyrones A (<b>1</b>) and D (<b>4</b>) demonstrate moderate anti-inflammatory activity, positioning 4-hydroxy-5,6-dihydro-2-pyrone core as a promising building block for the development of dual-function agents capable of concurrently addressing both conventional and drug-resistant bacterial infections while alleviating associated inflammatory responses.