WQ-3810 inhibits DNA gyrase activity in ofloxacin-resistant Mycobacterium leprae

Abstract

BackgroundMycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin. Methodology/principal findingsHere we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico.Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead. Conclusions/significanceThe inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.

Interaction of Quinolones Carrying New R1 Group with Mycobacterium leprae DNA Gyrase

“…12,20 In the previous study, to elucidate the potential of WQ-3810 as a drug for leprosy, its inhibitory effect against DNA gyrases of M. leprae was assessed instead of measuring the minimum inhibitory concentration. 14 This approach was used because M. leprae is yet to be cultured in artificial media. The IC 50 , calculated using a supercoiling inhibitory assay, was used as a reliable criterion for the therapeutic potency of fluoroquinolones against M. leprae.…”

“…In a subsequent in silico study, WQ-3810 showed an additional association with GyrB that may enhance its inhibitory effect on quinoloneresistant DNA gyrases bearing GyrA amino acid substitutions. 14 For a better understanding of this assumption, an additional comparison with WQ compounds having different R1 and R8 groups was deemed necessary.…”

“…1 Relapse cases especially are a serious concern because of a higher possibility of being accompanied by resistance to anti-leprosy drugs, and hence, limiting the number of drugs available for the treatment of leprosy. [11][12][13][14][15][16] To better treat MDT-resistant leprosy, alternative drugs are needed. A fluoroquinolone, ofloxacin (OFX), is currently being used for the treatment of MDT-resistant leprosy.…”

“…[11][12][13] Furthermore, it was shown to have strong inhibitory activity against M. leprae DNA gyrase with quinolone-resistant amino acid substitutions in GyrA. 14 This superior inhibitory property may be enhanced by the structural characteristic of the R1 group. 14 Thus, understanding the contribution of the R1 group to the inhibitory activity against M. leprae DNA gyrase seemed to be necessary.…”

“…14 This superior inhibitory property may be enhanced by the structural characteristic of the R1 group. 14 Thus, understanding the contribution of the R1 group to the inhibitory activity against M. leprae DNA gyrase seemed to be necessary.…”