Significance
The rapid emergence of multidrug-resistant bacteria is one of the greatest threats to global public health, demanding rapid delivery of new therapies to save patient lives. However, the development and clinical rollout of novel drug classes is a slow process that is unlikely to deliver a timely solution to this crisis. The reengineering of clinically approved antibiotics to evade resistance mechanisms offers a potential near- to short-term solution that takes advantage of established supply chains and clinical success. In this vein, we have designed and synthesized a unique class of shapeshifting vancomycin dimers that evade resistance acquisition, paving the way for future studies into shapeshifting antibiotic drugs to aid in the fight against resistant pathogens — including deadly VRE and MRSA.
Abstract
The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.
Alessandra Ottonello, Jessica A. Wyllie, Oussama Yahiaoui and John E. Moses
