Abstract
BackgroundOfloxacin is a fluoroquinolone (FQ) used for the treatment of leprosy. FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme. Mutations conferring FQ resistance have been reported to be found only in the gene encoding A subunit of this enzyme (gyrA) of M. leprae, although there are many reports on the FQ resistance-associated mutation in gyrB in other bacteria, including M. tuberculosis, a bacterial species in the same genus as M. leprae.Methodology/Principal FindingsTo reveal the possible contribution of mutations in gyrB to FQ resistance in M. leprae, we examined the inhibitory activity of FQs against recombinant DNA gyrases with amino acid substitutions at position 464, 502 and 504, equivalent to position 461, 499 and 501 in M. tuberculosis, which are reported to contribute to reduced sensitivity to FQ. The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502. Additionally, effectiveness of sitafloxacin, a FQ, to mutant DNA gyrases was revealed by low inhibitory concentration of this FQ.SignificanceData obtained in this study suggested the possible emergence of FQ-resistant M. leprae with mutations in gyrB and the necessity of analyzing both gyrA and gyrB for an FQ susceptibility test. In addition, potential use of sitafloxacin for the treatment of problematic cases of leprosy by FQ resistant M. leprae was suggested.
Highlights
Leprosy is one of the oldest human infectious diseases and remains a public health problem
Since the late 1990s, multi-drug resistant (MDR) isolates of M. leprae, resistant to RIF and DDS, have emerged and the importance of OFX has been a focus for the treatment of MDR-leprosy [3]; their use for leprosy and for other infectious diseases including tuberculosis has already led to OFX resistance in M. leprae [4,5,6,7,8]
We focused on amino acid substitutions at position 464, 502 and 504 in GyrB in M. leprae equivalent to 461, 499 and 501, respectively, in M. tuberculosis, as amino acid substitutions at these positions in M. tuberculosis are known to contribute to FQ resistance [13,14,15,16,20,22,23]
Summary
Leprosy is one of the oldest human infectious diseases and remains a public health problem. Since the late 1990s, multi-drug resistant (MDR) isolates of M. leprae, resistant to RIF and DDS, have emerged and the importance of OFX has been a focus for the treatment of MDR-leprosy [3]; their use for leprosy and for other infectious diseases including tuberculosis has already led to OFX resistance in M. leprae [4,5,6,7,8]. M. leprae has only DNA gyrase [11], which is the sole target of FQs. Genetic analysis of M. leprae clinical isolates revealed reduced FQ sensitivity associated with amino acid substitutions only at position 89 or 91 and 205 in GyrA and GyrB, respectively [4,5,6,7,8,12]. Mutations conferring FQ resistance have been reported to be found only in the gene encoding A subunit of this enzyme (gyrA) of M. leprae, there are many reports on the FQ resistance-associated mutation in gyrB in other bacteria, including M. tuberculosis, a bacterial species in the same genus as M. leprae
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