A Novel Pyrazinone Derivative with Anti-MRSA Activity, Produced by Streptomyces anulatus Isolated from the Rhizosphere of Malus trilobata in Lebanon

Antimicrobial resistance (AMR) poses a significant global health threat, largely driven by the overuse and misuse of antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant pathogen, remains a critical target for novel antibiotic development. This study explores the rhizosphere of the wild apple tree (Malus trilobata) in Lebanon as a potential source of antibacterial compounds. A bacterial strain, MR7S4, identified as Streptomyces anulatus, was isolated and characterized. Its crude extracts exhibited potent activity against Gram-positive pathogens, with minimum inhibitory concentration (MIC) values of 2 µg/mL against S. aureus ATCC 29213, S. aureus Newman, and S. aureus N315 (MRSA), and of 1 µg/mL against Enterococcus faecalis ATCC 19433. Bio-guided fractionation and structural analysis identified a novel antibacterial pyrazinone derivative, MR7S4-F3. This compound demonstrated MIC values of 4–16 µg/mL against Bacillus subtilis ATCC 6633, multiple S. aureus strains, E. faecalis ATCC 19433, E. faecium DSM 17050 (VRE), and E. faecium DSM 20478, while exhibiting no activity against Gram-negative bacteria. Whole-genome sequencing of MR7S4 revealed 35 biosynthetic gene clusters, underscoring its potential for natural product discovery. These findings highlight the untapped microbial diversity of the Middle East and North Africa (MENA) region as a valuable reservoir for antibiotic discovery. MR7S4-F3 emerges as a promising bioactive scaffold, addressing the urgent need for new therapeutic options to combat AMR.