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J Antimicrob Chemother ; 62(4): 713-9, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18587134

RESUMO

OBJECTIVES: The aim of this study was to determine the in vitro activity of lipiarmycin against drug-resistant strains of Mycobacterium tuberculosis (MTB) and to establish the resistance mechanism of MTB against lipiarmycin using genetic approaches. METHODS: MIC values were measured against a panel of drug-resistant strains of MTB using the broth microdilution method. Spontaneous lipiarmycin-resistant mutants of MTB were tested for cross-resistance to standard anti-TB drugs, and their rpoB and rpoC genes were sequenced to identify mutations. RESULTS: Lipiarmycin exhibited excellent inhibitory activity against multidrug-resistant strains of MTB with MIC values of <0.1 mg/L. Sequence analysis of the rpoB and rpoC genes from spontaneous lipiarmycin-resistant mutants of MTB revealed that missense mutations in these genes caused resistance to lipiarmycin. Although both lipiarmycin and rifampicin are known to inhibit the bacterial RNA polymerase, the sites of mutation in the rpoB gene were found to be different in MTB strains resistant to these inhibitors. Whereas all six rifampicin-resistant MTB strains tested had mutation in the 81 bp hotspot region of the rpoB gene spanning codons 507-533, 16 of 18 lipiarmycin-resistant strains exhibited mutation between codons 977 and 1150. The remaining two lipiarmycin-resistant strains had mutation in the rpoC gene. CONCLUSIONS: Lipiarmycin has excellent bactericidal activity against MTB and lacks cross-resistance to standard anti-TB drugs. Furthermore, rifampicin-resistant strains remained fully susceptible to lipiarmycin, and none of the lipiarmycin-resistant MTB strains became resistant to rifampicin, highlighting the lack of cross-resistance.


Assuntos
Aminoglicosídeos/farmacologia , Antituberculosos/farmacologia , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adaptação Biológica , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Proteínas de Bactérias/genética , Análise Mutacional de DNA , DNA Bacteriano/química , DNA Bacteriano/genética , Fidaxomicina , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/farmacologia , Alinhamento de Sequência , Análise de Sequência de DNA
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