• • Compound 1 (callinuene A) inhibits S. aureus ATCC29213 and MRSA T144 with MIC = 8 μg/mL, a 2-fold lower concentration than oxacillin against MRSA T144 (16 μg/mL) and 4-fold lower than oxacillin against E. coli strains (32 μg/mL). This selectivity index—8 μg/mL against Gram-positives versus >128 μg/mL against Gram-negatives—suggests a narrow-spectrum mechanism that could spare gut microbiota and reduce resistance pressure compared to broad-spectrum β-lactams.
• • Compound 2 (monasuslunin) shows MIC = 64 μg/mL against both S. aureus and MRSA, an 8-fold weaker potency than compound 1. This 8-fold gap between a monoterpene ester (1) and a sesquiterpenoid (2) indicates that the (Z)-2-methyl-6-methyleneocta-2,7-dien-1-yl (E)-3-(4-hydroxyphenyl)acrylate scaffold is critical for activity, providing a structure-activity relationship anchor for synthetic optimization.
• • Compounds 3–5 exhibit MIC >128 μg/mL against all four bacterial strains, including MRSA T144. The complete loss of activity in these sesquiterpenoids—despite structural similarity to compound 2—demonstrates that the bicyclic and eudesmane frameworks are inactive against MRSA, eliminating them as leads and conserving research resources for the monoterpene class.
• • Meropenem retains potent activity against MRSA T144 (MIC = 2 μg/mL) and E. coli strains (MIC <0.25 μg/mL), whereas oxacillin is ineffective against MRSA T144 (MIC = 16 μg/mL) and E. coli (MIC = 32 μg/mL). The 8-fold MIC advantage of meropenem over compound 1 against MRSA T144 (2 vs. 8 μg/mL) sets a clear benchmark: clinical translation of callinuene A requires either potency enhancement or use in combination therapy to compete with last-line carbapenems.