Besier, Silke;
Zander, Johannes;
Kahl, Barbara C.;
Kraiczy, Peter;
Brade, Volker;
Wichelhaus, Thomas A.
The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates
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Medientyp:
E-Artikel
Titel:
The Thymidine-Dependent Small-Colony-Variant Phenotype Is Associated with Hypermutability and Antibiotic Resistance in Clinical Staphylococcus aureus Isolates
Beteiligte:
Besier, Silke;
Zander, Johannes;
Kahl, Barbara C.;
Kraiczy, Peter;
Brade, Volker;
Wichelhaus, Thomas A.
Erschienen:
American Society for Microbiology, 2008
Erschienen in:Antimicrobial Agents and Chemotherapy
Beschreibung:
<jats:title>ABSTRACT</jats:title>
<jats:p>
Thymidine-dependent small-colony variants (TD-SCVs) of
<jats:italic>Staphylococcus aureus</jats:italic>
can be isolated from the airway secretions of patients suffering from cystic fibrosis (CF) and are implicated in persistent and treatment-resistant infections. These characteristics, as well as the variety of mutations in the thymidylate synthase-encoding
<jats:italic>thyA</jats:italic>
gene which are responsible for thymidine dependency, suggest that these morphological variants are hypermutable. To prove this hypothesis, we analyzed the mutator phenotype of different
<jats:italic>S. aureus</jats:italic>
phenotypes, in particular CF-derived TD-SCVs, CF-derived isolates with a normal phenotype (NCVs), and non-CF NCVs. The comparative analysis revealed that the CF isolates had significantly higher mutation rates than the non-CF isolates. The TD-SCVs, in turn, harbored significantly more strong hypermutators (mutation rate ≥ 10
<jats:sup>−7</jats:sup>
) than the CF and non-CF NCVs. In addition, antimicrobial resistance to non-beta-lactam antibiotics, including gentamicin, ciprofloxacin, erythromycin, fosfomycin, and rifampin, was significantly more prevalent in TD-SCVs than in CF and non-CF NCVs. Interestingly, macrolide resistance, which is usually mediated by mobile genetic elements, was conferred in half of the macrolide-resistant TD-SCVs by the point mutation A2058G or A2058T in the genes encoding the 23S rRNA. Sequence analysis of
<jats:italic>mutS</jats:italic>
and
<jats:italic>mutL</jats:italic>
, which are involved in DNA mismatch repair in gram-positive bacteria, revealed that in hypermutable CF isolates and especially in TD-SCVs,
<jats:italic>mutL</jats:italic>
was often truncated due to frameshift mutations. In conclusion, these data provide direct evidence that TD-SCVs are hypermutators. This hypermutability apparently favors the acquisition of antibiotic resistance and facilitates bacterial adaptation during long-term persistence.
</jats:p>