Antibiotics of the future are prone to resistance in Gram-negative pathogens

Despite the ongoing development of new antibiotics, the future evolution of bacterial resistance may render them ineffective. We demonstrate that antibiotic candidates currently under development are as prone to resistance evolution in Gram-negative pathogens as clinically employed antibiotics. Resistance generally stems from both genomic mutations and the transfer of antibiotic resistance genes from microbiomes associated with humans, both factors carrying equal significance. The molecular mechanisms of resistance overlap with those found in commonly used antibiotics. Therefore, these mechanisms are already prevalent in natural populations of pathogens, indicating that resistance can rapidly emerge through selection of pre-existing bacterial variants. Additionally, resistance to new peptide-based antibiotics enhances bacterial virulence, raising concerns. However, certain combinations of antibiotics and bacterial strains are less prone to developing resistance, emphasising the potential of narrow-spectrum antibacterial therapies that could remain effective. Our comprehensive framework allows predicting the future health risks associated with bacterial resistance to new antibiotics.