Cytochromes P450: novel drug targets in the war against multidrug-resistant Mycobacterium tuberculosis

Munro, Andrew W.; McLean, Kirsty J.; Marshall, Khiya J.; Warman, Ashley J.; Lewis, George T.; Roitel, Olivier; Sutcliffe, Michael J.; Kemp, Carol A.; Modi, Sandeep; Scrutton, NS; Leys, D.

doi:10.1042/bst0310625

Cited by 28 publications

(18 citation statements)

References 27 publications

(36 reference statements)

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“…CPZ has been proposed to inhibit respiration (42,43), although other mechanisms have been proposed (44). Azoles are known to bind to the heme iron in cytochrome P450s, specifically the CYP51 sterol demethylase in fungi and possibly the CYP121 in M. tuberculosis as has been suggested (41,45).…”

Section: Regulation Of Respiratory Chain Components and The Mode Of Amentioning

confidence: 99%

The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism

Boshoff

Myers

Copp

et al. 2004

Journal of Biological Chemistry

577

551

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The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen.

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Section: Regulation Of Respiratory Chain Components and The Mode Of Amentioning

confidence: 99%

The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism

Boshoff

Myers

Copp

et al. 2004

Journal of Biological Chemistry

577

551

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“…In these bacteria, P450s are typically involved in the initial catabolism of growth substrates and in secondary metabolite biosynthesis. Given the high number of P450s in Mtb and their susceptibility to azole drugs, this class of enzyme has been proposed as a promising target for antimycobacterial therapeutic development (2). However, the function of most mycobacterial P450s has yet to be determined.…”

mentioning

confidence: 99%

“…P450s are heme-dependent mono-oxygenases that utilize reducing equivalents from NAD(P)H relayed via electron transfer proteins to activate heme-bound O 2 . Typical of actinomycete genomes, that of Mtb includes 20 genes encoding P450s (2). In these bacteria, P450s are typically involved in the initial catabolism of growth substrates and in secondary metabolite biosynthesis.…”

mentioning

confidence: 99%

Mycobacterial Cytochrome P450 125 (Cyp125) Catalyzes the Terminal Hydroxylation of C27 Steroids

Capyk

Kalscheuer

Stewart

et al. 2009

Journal of Biological Chemistry

161

172

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Mycobacterium tuberculosis (Mtb)4 infects one-third of the human population and is the leading cause of lethal bacterial infections worldwide. Synergy of Mtb with the HIV virus and the emergence of extensively drug-resistant Mtb strains (XDR-TB) have further emphasized this pathogen as a major global health threat (1). However, understanding of many of its key physiological processes, particularly those contributing to intracellular survival, is limited. One element of Mtb physiology that may prove important for therapeutic development is its unusually high number of cytochromes P450 (P450s). P450s are heme-dependent mono-oxygenases that utilize reducing equivalents from NAD(P)H relayed via electron transfer proteins to activate heme-bound O 2 . Typical of actinomycete genomes, that of Mtb includes 20 genes encoding P450s (2). In these bacteria, P450s are typically involved in the initial catabolism of growth substrates and in secondary metabolite biosynthesis. Given the high number of P450s in Mtb and their susceptibility to azole drugs, this class of enzyme has been proposed as a promising target for antimycobacterial therapeutic development (2). However, the function of most mycobacterial P450s has yet to be determined.The gene encoding one Mtb P450, cyp125 (Rv3545c), belongs to a large cluster of genes encoding cholesterol degradation (3). This cluster is conserved in several actinobacteria including the non-pathogenic soil bacterium, Rhodococcus jostii RHA1. The genes encode functions necessary for cholesterol import (4), as well as for the degradation of the steroid side chain and rings A and B (3). Several of the ring degradation enzymes from Mtb have been characterized biochemically (5-9). Animal infection studies of mutants deficient in cholesterol uptake and catabolism have indicated that cholesterol metabolism in Mtb plays an important role in infection, contributing to both dissemination in the host (7) and persistence (9, 10). These results are consistent with several mutant screens, which previously identified numerous genes in the cholesterol degradation pathway as having an impact on intracellular growth and survival in both mouse and macrophage models (11, 12), implicating cholesterol catabolism in Mtb pathogenicity.Cyp125 has been implicated in the in vivo survival of Mtb, although its catalytic activity has not been demonstrated, and its physiological role remains unclear. The cyp125 gene is upregulated during growth of Mtb in interferon ␥-activated macrophages (13)

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“…11,12 The spatial disposition of compounds 26 and 36 was observed to be similar to that of fluconazole ( Figure 3A). Compound 26 exhibits maximum interactions with important active site residues ( Figure 3B).…”

Section: * S Supporting Informationmentioning

confidence: 82%

Identification of 1-[4-Benzyloxyphenyl)-but-3-enyl]-1H-azoles as New Class of Antitubercular and Antimicrobial Agents

Anand

Ramakrishna

Gupt

et al. 2013

ACS Med. Chem. Lett.

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A series of 1-[(4-benzyloxyphenyl)-but-3-enyl]-1H-azoles has been identified as potent antitubercular agents against Mycobacterium tuberculosis. Synthesis of compounds involved acid catalyzed ring-opening of cyclopropyl ring of phenyl cyclopropyl methanols followed by nucleophilic attack of the azoles on the carbocation intermediates. Several of the compounds 26, 34, and 36 exhibited significant antitubercular activities with MIC value as low as 1.56, 1.56, and 0.61 μg/ mL, respectively, comparable to many standard drugs. These compounds were also screened against other strains of bacteria and fungi, and few of them showed good antifungal activity against A. f umigatus, responsible for lung infection. KEYWORDS: Antitubercular agents, azoles, cyclopropyl methanols, Mycobacterium tuberculosis Mycobacterium tuberculosis (Mtb) causing tuberculosis is one of humanity's oldest and most resilient plagues, despite the availability of a four drug (INH, ethambutol, pyrazinamide, and rifampicin) regimen to treat the disease. 1 The long duration of therapy generally results in noncompliance of the treatment and results in multidrug resistance tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), which are highly lethal, extremely expensive and complicated to treat, posing new challenges for the prevention, treatment, and control of TB. 2−4 As per WHO, reported in 2011, about 8.7 million new cases of TB (13% coinfected with HIV) were reported with 1.4 million mortality. The latter include almost one million deaths among HIV-negative individuals and 430 000 among HIV-positive people. 5 Because of the drug−drug interactions, difficulty of the coadministration of anti-TB and anti-HIV drugs posed a new challenge before scientific community. 6 Despite the unraveling of mycobacterial genome sequence 7 and sound knowledge of mycobacterial biochemistry, none of the antitubercular drugs entered in the market for the last 50 years except a diraylquinoline (TMC 207) from Johnson & Johnson only very recently. 8,9 Unavailability of suitable vaccine and limitation of existing anti-TB drugs warrants the introduction of novel compounds or drug regimen effective against both the actively growing and latent stage mycobacterium avoiding drug−drug interactions.Azole and triazole based compounds are good as antifungal and antimycobacterial agents. 10 Such compounds generally inhibit cytochrome P450 (CYP121), an important enzyme with several of its isoforms of great significance in M. tuberculosis viability and pathogenicity. 11,12 Azoles also inhibit the biosynthesis of glycopeptidolipids (GPLs), an integral part of the mycobacterial cell envelope. 13 In an ongoing program for design and development of new antitubercular agents 14−17 we have identified phenyl cyclopropyl methanones and methanols as potent leads. 16,17 One of the phenyl cyclopropyl methanols (A) showed very good in vitro activity (MIC 3.12 μg/mL) against susceptible and drug resistant strains of M. Tuberculosis, and it exhibited marginal in vivo a...

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Cytochromes P450: novel drug targets in the war against multidrug-resistant Mycobacterium tuberculosis

Cited by 28 publications

References 27 publications

The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism

The Transcriptional Responses of Mycobacterium tuberculosis to Inhibitors of Metabolism

Mycobacterial Cytochrome P450 125 (Cyp125) Catalyzes the Terminal Hydroxylation of C27 Steroids

Identification of 1-[4-Benzyloxyphenyl)-but-3-enyl]-1H-azoles as New Class of Antitubercular and Antimicrobial Agents

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