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Antimicrobial Agents and Chemotherapy, January 1998, p. 121-128, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Mutations in Topoisomerase IV and DNA Gyrase of
Staphylococcus aureus: Novel Pleiotropic Effects on
Quinolone and Coumarin Activity
Bénédicte
Fournier and
David C.
Hooper*
Infectious Disease Division and Medical
Services, Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts 02114-2696
Received 28 July 1997/Returned for modification 20 September
1997/Accepted 30 October 1997
Previous studies have shown that topoisomerase IV and DNA gyrase
interact with quinolones and coumarins in different ways. The MICs of
coumarins (novobiocin and coumermycin) for MT5, a Staphylococcus
aureus nov mutant, are higher than those for wild-type strains.
Sequencing the gyrB gene encoding one subunit of the DNA
gyrase revealed the presence of a double mutation likely to be
responsible for this resistance: at codon 102 (Ile to Ser) and at codon
144 (Arg to Ile). For single-step flqA mutant MT5224c9, previously selected on ciprofloxacin, the fluoroquinolone
MIC was higher and the coumarin MIC was lower than those for its
parent, MT5. Sequencing the grlB and
grlA genes of topoisomerase IV of MT5224c9 showed a single
Asn-470-to-Asp mutation in GrlB. Genetic outcrosses by transformation
with chromosomal DNA and introduction of plasmids carrying either the
wild-type or the mutated grlB gene indicated that this
mutation causes both increased MICs of fluoroquinolones
and decreased MICs of coumarins and that the mutant grlB
allele is codominant for both phenotypes
with multicopy alleles. Integration of these plasmids into the
chromosome confirmed the codominance of fluoroquinolone resistance, but
grlB+ appeared dominant over grlB
(Asp-470) for coumarin resistance. Finally, the gyrA
(Leu-84) mutation previously described as silent for fluoroquinolone
resistance increased the MIC of nalidixic acid, a nonfluorinated
quinolone. Combining the grlA (Phe-80) and grlB
(Asp-470) mutations with this gyrA mutation also had differing effects. The findings indicate that alterations in
topoisomerases may have pleiotropic effects on different classes of
inhibitors as well as on inhibitors within the same class. A full
understanding of drug action and resistance at the molecular level must
take into account both inhibitor structure-activity relationships and the effects of different classes of topoisomerase mutants.
*
Corresponding author. Mailing address: Infectious
Disease Division, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114-2696. Phone: (617) 726-3812. Fax: (617) 726-7416. E-mail: hooper.david{at}mgh.harvard.edu.
Antimicrobial Agents and Chemotherapy, January 1998, p. 121-128, Vol. 42, No. 1
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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