1887

Abstract

The genome sequence of has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of have indicated that these actinomycetes also have large complements of P450s, pointing to important physiological roles for these enzymes. The actinomycete P450s include homologues of 14α-sterol demethylases, the targets for the azole class of drugs in yeast and fungi. Previously, this type of P450 was considered to be absent from bacteria. When present at low concentrations in growth medium, azole antifungal drugs were shown to be potent inhibitors of the growth of and of strains, indicating that one or more of the P450s in these bacteria were viable drug targets. The drugs econazole and clotrimazole were most effective against (MIC values of <02 and 03 μM, respectively) and were superior inhibitors of mycobacterial growth compared to rifampicin and isoniazid (which had MIC values of 12 and 365 μM, respectively). In contrast to their effects on the actinomycetes, the azoles showed minimal effects on the growth of , which is devoid of P450s. Azole drugs coordinated tightly to the haem iron in H37Rv P450s encoded by genes (the sterol demethylase CYP51) and (CYP121). However, the azoles had a higher affinity for CYP121, with values broadly in line with the MIC values for . This suggested that CYP121 may be a more realistic target enzyme for the azole drugs than CYP51, particularly in light of the fact that an Δ strain was viable and showed little difference in its sensitivity to azole drugs compared to the wild-type. If the azole drugs prove to inhibit a number of important P450s in and , then the likelihood of drug resistance developing in these species should be minimal. This suggests that azole drug therapy may provide a novel antibiotic strategy against strains of that have already developed resistance to isoniazid and other front-line drugs.

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2002-10-01
2019-12-06
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