Diaminodiphenylsulfone resistance ofMycobacterium lepraedue to mutations in the dihydropteroate synthase gene

Abstract

The nucleotide sequence analysis of the dihydropteroate synthase (DHPS) gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains revealed that the mutation was limited at highly conserved amino acid residues 53 or 55. Though the mutation at amino acid residue 55 or its homologous site has been reported in other bacteria, the mutation at residue 53 is the first case in bacteria. This is the first paper which links the mutations in DHPS and sulfonamide resistance in M. leprae. This finding is medically and socially relevant, since leprosy is still a big problem in certain regions.

A novel method for simple detection of mutations conferring drug resistance in Mycobacterium leprae, based on a DNA microarray, and its applicability in developing countries

“…A total of 84 isolates without mutation in the folP1 gene were susceptible to dapsone, but one isolate was resistant with intermediate degree and five isolates were resistant with low degree (Cambau et al, 2006). On the other hand, a total of 24 isolates resistant to dapsone with high or intermediate degree revealed amino acid substitution at the DRDR of the fop1 gene (Kai et al, 1999;Matsuoka et al, 2000Matsuoka et al, , 2003Matsuoka et al, , 2007Williams et al, 2000;Lee et al, 2001;Maeda et al, 2001;Cambau et al, 2006). An isolate with mutation ACC to GCC at codon 53 was demonstrated to be resistant with low degree (Cambau et al, 2006), though it is not clear whether dapsone resistance with low degree is true resistance (Matsuoka et al, 2007).…”

“…In addition, mutations in the folP1 gene, encoding dihydrofolate synthetase, have been shown to be responsible for dapsone resistance (Kai et al, 1999;Matsuoka et al, 2000Matsuoka et al, , 2003Matsuoka et al, , 2007Williams et al, 2000;Lee et al, 2001;Maeda et al, 2001;Cambau et al, 2006). The prevalence of drug resistance in selected areas was surveyed through the application of molecular analysis to detect mutations conferring drug resistance (Matsuoka et al, 2007).…”

Strategies for potentiation of ethionamide and folate antagonists againstMycobacterium tuberculosis

“…In fact, it has been shown in other bacteria commonly treated with sulfonamides that a single point mutation at conserved residues corresponding to serine 53 or proline 55 of M. tuberculosis DHPS confers complete sulfonamide resistance [85,86]. Resistant strains of Mycobacterium leprae with these mutations have been isolated, indicating the possibility that M. tuberculosis may rapidly acquire them as well [85,86].…”

Dihydropteroate Synthase Gene Mutations inPneumocystisand Sulfa Resistance

“…Based on homology to the E. coli DHPS, these point mutations appear to be in an active site of the enzyme involved in substrate binding; thus, amino acid substitutions in these regions could result in structural changes that could interfere with substrate binding and enzyme activity ( 21 ). Likewise, similar point mutations in positions equivalent to this site in Plasmodium falciparum ( 15 ) and Mycobacterium leprae ( 28 ) confer sulfa resistance. Other mutations near this site also cause sulfa resistance in S. pneumoniae and P. falciparum ( 18 ).…”