Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes

KJ McLean; Ker R Marshall; A Richmond; Iain S Hunter; Kay Fowler; Tobias Kieser; Sudagar S Gurcha; Gurydal S Besra; Andrew W Munro

doi:10.1099/00221287-148-10-2937

Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes

KJ McLean, Ker R Marshall, A Richmond, Iain S Hunter, Kay Fowler, Tobias Kieser, Sudagar S Gurcha, Gurydal S Besra, Andrew W Munro^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

167 Citations (Scopus)

Abstract

The genome sequence of Mycobacterium tuberculosis has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of Streptomyces coelicolor 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 14alpha-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 Mycobacterium smegmatis and of Streptomyces 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 M. smegmatis (MIC values of

Original language	English
Pages (from-to)	2937-2949
Number of pages	13
Journal	Microbiology
Volume	148
Issue number	10
DOIs	https://doi.org/10.1099/00221287-148-10-2937
Publication status	Published - Oct 2002
Externally published	Yes

Keywords

tuberculosis
azole drugs
CYP121
P450 inhibitors
COMPLETE GENOME SEQUENCE
STEROL 14-DEMETHYLASE P450
DRUG-RESISTANCE
ACTIVE-SITE
TUBERCULOSIS
CYP51
14-ALPHA-DEMETHYLASE
DERIVATIVES
MECHANISMS
SMEGMATIS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1099/00221287-148-10-2937

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title = "Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes",

abstract = "The genome sequence of Mycobacterium tuberculosis has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of Streptomyces coelicolor 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 14alpha-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 Mycobacterium smegmatis and of Streptomyces 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 M. smegmatis (MIC values of",

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author = "KJ McLean and Marshall, {Ker R} and A Richmond and Hunter, {Iain S} and Kay Fowler and Tobias Kieser and Gurcha, {Sudagar S} and Besra, {Gurydal S} and Munro, {Andrew W}",

year = "2002",

month = oct,

doi = "10.1099/00221287-148-10-2937",

language = "English",

volume = "148",

pages = "2937--2949",

journal = "Microbiology ",

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publisher = "Society for General Microbiology",

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TY - JOUR

T1 - Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes

AU - McLean, KJ

AU - Marshall, Ker R

AU - Richmond, A

AU - Hunter, Iain S

AU - Fowler, Kay

AU - Kieser, Tobias

AU - Gurcha, Sudagar S

AU - Besra, Gurydal S

AU - Munro, Andrew W

PY - 2002/10

Y1 - 2002/10

N2 - The genome sequence of Mycobacterium tuberculosis has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of Streptomyces coelicolor 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 14alpha-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 Mycobacterium smegmatis and of Streptomyces 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 M. smegmatis (MIC values of

AB - The genome sequence of Mycobacterium tuberculosis has revealed the presence of 20 different cytochrome P450 mono-oxygenases (P450s) within this organism, and subsequent genome sequences of other mycobacteria and of Streptomyces coelicolor 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 14alpha-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 Mycobacterium smegmatis and of Streptomyces 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 M. smegmatis (MIC values of

KW - tuberculosis

KW - azole drugs

KW - CYP121

KW - P450 inhibitors

KW - COMPLETE GENOME SEQUENCE

KW - STEROL 14-DEMETHYLASE P450

KW - DRUG-RESISTANCE

KW - ACTIVE-SITE

KW - TUBERCULOSIS

KW - CYP51

KW - 14-ALPHA-DEMETHYLASE

KW - DERIVATIVES

KW - MECHANISMS

KW - SMEGMATIS

U2 - 10.1099/00221287-148-10-2937

DO - 10.1099/00221287-148-10-2937

M3 - Article

SN - 1350-0872

VL - 148

SP - 2937

EP - 2949

JO - Microbiology

JF - Microbiology

IS - 10

ER -

Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes

Abstract

Keywords

UN SDGs

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