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Daptomycin is a last-line antibiotic used in the treatment of multidrug-resistant  Enterococcus faecium  infections. Alarmingly, daptomycin-resistant  E. faecium  isolates have emerged. In this study, we investigated the evolution and mechanisms of daptomycin resistance in clinical  E. faecium  isolates and the corresponding acquisition of collateral sensitivity (CS) as an evolutionary trade-off. We evolved daptomycin resistance in six daptomycin-susceptible  E. faecium  isolates to obtain daptomycin-resistant mutants. The six  E. faecium  strains successfully acquired high-level resistance to daptomycin  in vitro , but this led to fitness costs in terms of growth,  in vitro  competition, and virulence. Mutations in  liaFSR ,  yycFG , and  cls ; increased surface positive charge; thicker cell walls; and elevated expression of  dltABCD  and  tagGH  were observed in daptomycin-resistant mutants. Surprisingly, we observed the emergence of CS in SC1762 isolates after the induction of daptomycin resistance. Compared with parental strains, the SC1174-D strain (i.e., daptomycin-resistant mutant of SC1174; non-CS) showed significantly upregulated expression of the  vanA  gene cluster. However, in SC1762-D (i.e., daptomycin-resistant mutant of SC1762), all  vanA  cluster genes except the  vanX  gene were obviously downregulated. Further  in silico  analyses revealed that an IS 1216E- based composite transposon was generated in SC1762-D, and it disrupted the  vanH  gene, likely affecting the structure and expression of the  vanA  gene cluster and resulting in resensitization to glycopeptides. Overall, this study reports a novel form of CS between daptomycin and glycopeptides in  E. faecium . Further, it provides a valuable foundation for developing effective regimens and sequential combinations of daptomycin and glycopeptides against  E. faecium .

Acquisition of Daptomycin Resistance by Enterococcus faecium Confers Collateral Sensitivity to Glycopeptides