AUTHOR=Zeng Weiliang , Feng Luozhu , Qian Changrui , Chen Tao , Wang Sipei , Zhang Ying , Zheng Xiangkuo , Wang Lingbo , Liu Shixing , Zhou Tieli , Sun Yao 

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

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.815600

DOI=10.3389/fmicb.2022.815600

ISSN=1664-302X

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