A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h.