Medicinal plants are an essential source of traditional curatives for numerous
skin diseases. Polyalthia longifolia (Sonn.) Thwaites (Annonaceae family) is a medicinal plant used to cure skin illnesses. P. longifolia is usually applied in folkloric therapeutical systems to treat
skin diseases. The methicillin-resistant Staphylococcus aureus (MRSA) bacteria is among the essential bacteria contributing to
skin diseases. Hence, to verify the traditional medicinal claim of P. longifolia usage in
skin disease treatment, the current research was performed to study the synergistic antibacterial activity of standardized Polyalthia longifolia
methanol leaf extract (MEPL) against MRSA bacteria. The synergistic antimicrobial activity result of
ceftriaxone, when mixed with MEPL, against MRSA was investigated by the disc diffusion method, broth microdilution method, checkerboard dilution test, and modulation of
mecA gene expression by multiplex polymerase chain reaction (multiplex PCR). The MEPL extract exhibited good synergistic antimicrobial activity against MRSA. Using the checkerboard method, we confirmed the synergistic effect of MEPL from P. longifolia and
ceftriaxone (2:1) for MRSA with a marked reduction of the MIC value of the
ceftriaxone from 8000 µg/mL to 1000 µg/mL. Moreover, the combination of MEPL with
ceftriaxone significantly (p < 0.05) inhibited the presence of the resistant
mecA gene in the tested strain. The LC-ESI-MS/MS analysis identified compounds that were reported to exhibit antimicrobial activity. Conclusively, the MEPL extract, an important etiological agent for
skin diseases, showed worthy synergistic antimicrobial action against MRSA bacteria, thus supporting the traditional use of P. longifolia.