New antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance

Several new antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not reached the market yet. We found that antibiotic resistance generally evolves rapidly in Staphylococcus aureus. Cross-resistance was detected between vancomycin, daptomycin and teixobactin, a promising antibiotic candidate. These patterns were driven by overlapping molecular mechanisms via mutations in two-component signalling systems. In particular, teixobactin resistant bacteria display clinically significant multi-drug resistance and cause invasive disease in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against new antibiotic candidates are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve rapidly from selection of pre-existing genetic variation. Our work highlights the importance of predicting future evolution of resistance to new antibiotic candidates at an early stage of drug development.