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Methionine sulfoxide reductase A (MsrA), an efflux pump belonging to ATP‐binding cassette (ABC) transporter family that conferred resistance to macrolides, was detected in Methicillin‐Resistant Staphylococcus aureus (MRSA) RN4220 strain. Herein we report isolation of phytoconstituents from Piper cubeba fruit methanol extract and investigated their efflux pump inhibitory potential against MsrA pump. Four isolated compounds viz. pellitorine, sesamin, piperic acid and tetrahydropiperine when studied in combination with erythromycin in S. aureus RN4220, exhibited 2‐8 fold reduction in Minimum inhibitory concentration (MIC) of erythromycin. Pellitorine and sesamin decreased MIC of erythromycin by 8‐fold. The real‐time fluorometry‐based efflux and accumulation studies of ethidium bromide (EtBr) on S. aureus RN4220 in the presence of these compounds showed reduced efflux and enhanced uptake, thus indicating inhibition of the efflux pump. Pellitorine showed significant post‐antibiotic effect of erythromycin. The results revealed that the primary mechanism of action of these compounds involves steady ATP production impairment.