Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients

G. J. Alangaden, E. K. Manavathu, S. B. Vakulenko, N. M. Zvonok, S. A. Lerner

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

To examine the mechanism of resistance to fluoroquinolones in Mycobacterium tuberculosis, we selected spontaneous fluoroquinolone-resistant mutants from a susceptible strain, H37Rv, and studied the susceptibilities of these mutants and two fluoroquinolone-resistant clinical isolates (A-382, A- 564) to various fluoroquinolones and to isoniazid and rifampin. Furthermore, since mutations within the quinolone resistance-determining region of the structural gene encoding the A subunit of DNA gyrase are the most common mechanism of acquired resistance, we amplified this region by PCR and compared the nucleotide sequences of the fluoroquinolone-resistant strains with that of the susceptible strain. Fluoroquinolone-resistant mutants of H37Rv appeared at frequencies of 2 x 10-6 to 1 x 10-8. For three mutants selected on ciprofloxacin, ofloxacin, and sparfloxacin, respectively, and the two clinical isolates, MICs of ciprofloxacin and ofloxacin were as high as 16 μg/ml, and those of sparfloxacin were 4 to 8 μg/ml. They displayed cross- resistance to all fluoroquinolones tested but not to isoniazid or rifampin. Sparfloxacin and FQ-A (PD 127391-0002) were the most potent fluoroquinolones. All of the fluoroquinolone-resistant strains (MICs, ≥4 μg/ml) had mutations in the quinolone resistance-determining region which led to substitution of the Asp residue at position 87 (Asp-87) by Asn or Ala or the substitution of Ala-83 by Val in the A subunit of DNA gyrase. Similar mutations have been noted in other bacterial species and recently in mycobacteria. The broad resistance to fluoroquinolones that arose readily by point mutation in the laboratory and apparently during inadequate therapy, as was the case in the clinical isolates, may ultimately lead to serious restriction of the use of these drugs in the treatment of tuberculosis.

Original languageEnglish (US)
Pages (from-to)1700-1703
Number of pages4
JournalAntimicrobial Agents and Chemotherapy
Volume39
Issue number8
DOIs
StatePublished - Jan 1 1995

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Fluoroquinolones
Mycobacterium tuberculosis
DNA Gyrase
Ofloxacin
Quinolones
Isoniazid
Rifampin
Ciprofloxacin
Mutation
Mycobacterium
Viperidae
Point Mutation
Tuberculosis
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. / Alangaden, G. J.; Manavathu, E. K.; Vakulenko, S. B.; Zvonok, N. M.; Lerner, S. A.

In: Antimicrobial Agents and Chemotherapy, Vol. 39, No. 8, 01.01.1995, p. 1700-1703.

Research output: Contribution to journalArticle

Alangaden, G. J. ; Manavathu, E. K. ; Vakulenko, S. B. ; Zvonok, N. M. ; Lerner, S. A. / Characterization of fluoroquinolone-resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. In: Antimicrobial Agents and Chemotherapy. 1995 ; Vol. 39, No. 8. pp. 1700-1703.
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