Antibacterial resistance is a pressing global health challenge that necessitates the development of new therapeutic agents. Phenylthiazole antibacterial agents have been extensively studied, by our group, as a potential novel class of antibiotics to circumvent the scourge of antibacterial resistance. Previously, the phenylthiazole lead compound 1 was shown to possess potent activity against clinical isolates of methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA). The promising activity of this novel class of antibiotics is hampered by their short half-life due to rapid hepatic metabolism. In the present study, a metabolic methylene soft spot in the lead 1 was identified and replaced with an oxygen atom. The newly developed phenylthiazoles, with alkoxy side chains, demonstrate high metabolic stability (t1/2 > 4 h), while maintaining their potent anti-MRSA activity. Furthermore, compound 5p demonstrated a selective advantage over vancomycin with its ability to kill intracellular MRSA.