The rapid emergence of multidrug-resistant bacteria is one of the greatest threats to global public health. Despite this, there is a significant decrease in the development of novel therapeutics, and deaths attributed to antibiotic resistance is expected to rise to over 10 million per year by 2050. We propose that the re-engineering of existing antibiotics using novel chemical strategies, such that their susceptibility to current resistance mechanisms is minimised, offers a timely approach to tackle this crisis. This study focuses on re-engineering the cell wall targeting antibiotic vancomycin; a drug of last resort for treating multidrug-resistant Gram-positive bacterial infections. Specifically, we explore the antibiotic potential of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that incorporate a dynamic bullvalene core. We show that SVDs display potent activity against drug-sensitive and resistant strains of enterococci, compared to vancomycin. The SVDs demonstrate minimum inhibitory concentration values between 4 and 32 µg/mL against strains where vancomycin is no longer a viable treatment option. When assessed in a Galleria mellonella infection model, the SVDs significantly improved survival rates of vancomycin-resistant enterococci infections relative to vancomycin using a standard clinical dose. Importantly, while resistance to vancomycin emerges in drug-sensitive strains following continuous exposure, resistance to the SVDs has not been observed under the same conditions tested. Thus, this study provides proof-of-concept that re-engineering existing antibiotics with a shapeshifting modality may be a viable approach to revitalise the antibiotic discovery pipeline and tackle antibiotic resistance.