Beschreibung:
<jats:title>ABSTRACT</jats:title>
<jats:p>
Tigecycline (TIG) is approved for use for the treatment of complicated intra-abdominal infections, skin and skin structure infections, as well as pneumonia. Acquired resistance or reduced susceptibility to TIG has been observed in Gram-negative rods, has seldom been reported in Gram-positive organisms, and has not yet been reported in
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Enterococcus faecium</jats:named-content>
. Using the serial passage method,
<jats:italic>in vitro</jats:italic>
mutant AusTig and
<jats:italic>in vitro</jats:italic>
mutants HMtig1 and HMtig2 with decreased TIG susceptibility (MICs, 0.25 μg/ml) were obtained from strains
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>
Aus0004 and HM1070 (MICs, 0.03 μg/ml), respectively. In addition, two vancomycin-resistant
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">E. faecium</jats:named-content>
clinical isolates (EF16 and EF22) with reduced susceptibility to TIG (MICs, 0.5 and 0.25 μg/ml, respectively) were studied. Compared to the wild-type strains, the
<jats:italic>in vitro</jats:italic>
mutants also showed an increase in the MICs of other tetracyclines. An efflux mechanism did not seem to be involved in the reduced TIG susceptibility, since the presence of efflux pump inhibitors (reserpine or pantoprazole) did not affect the MICs of TIG. Whole-genome sequencing of AusTig was carried out, and genomic comparison with the Aus0004 genome was performed. Four modifications leading to an amino acid substitution were found. These mutations affected the
<jats:italic>rpsJ</jats:italic>
gene (
<jats:italic>efau004_00094</jats:italic>
, coding for the S10 protein of the 30S ribosomal subunit),
<jats:italic>efau004_01228</jats:italic>
(encoding a cation transporter),
<jats:italic>efau004_01636</jats:italic>
(coding for a hypothetical protein), and
<jats:italic>efau004_02455</jats:italic>
(encoding the
<jats:sc>l</jats:sc>
-lactate oxidase). The four other strains exhibiting reduced TIG susceptibility were screened for the candidate mutations. This analysis revealed that three of them showed an amino acid substitution in the same region of the RpsJ protein. In this study, we characterized for the first time genetic determinants linked to reduced TIG susceptibility in enterococci.
</jats:p>