Antifungal agents: mechanisms of action

doi:10.1016/S0966-842X(03)00117-3

Trends in Microbiology

Volume 11, Issue 6, June 2003, Pages 272-279

https://doi.org/10.1016/S0966-842X(03)00117-3 Get rights and content

Abstract

Clinical needs for novel antifungal agents have altered steadily with the rise and fall of AIDS-related mycoses, and the change in spectrum of fatal disseminated fungal infections that has accompanied changes in therapeutic immunosuppressive therapies. The search for new molecular targets for antifungals has generated considerable research using modern genomic approaches, so far without generating new agents for clinical use. Meanwhile, six new antifungal agents have just reached, or are approaching, the clinic. Three are new triazoles, with extremely broad antifungal spectra, and three are echinocandins, which inhibit synthesis of fungal cell wall polysaccharides – a new mode of action. In addition, the sordarins represent a novel class of agents that inhibit fungal protein synthesis. This review describes the targets and mechanisms of action of all classes of antifungal agents in clinical use or with clinical potential.

Section snippets

New targets, new agents and clinical realities

The biomedical literature abounds with reports of macromolecules essential for fungal survival, growth, virulence or cellular morphogenesis that have been proposed as potential targets for novel antifungal agents. The arrival of whole-genome sequence data for pathogenic fungi, such as Candida albicans [1], Aspergillus fumigatus [2] and Cryptococcus neoformans [3], as well as for non-pathogens, such as Saccharomyces cerevisiae [4], has paved the way for discovery of genes encoding candidate

Griseofulvin

The earliest inhibitory agent specific to fungal species was griseofulvin (Fig. 2). The precise mechanism of action of this compound is still unknown [11], but the favoured explanation is that it interferes with microtubule assembly. The selective toxicity of griseofulvin for fungi is only moderate (liver toxicity is recognised as an occasional hazard) and its spectrum of action is restricted mainly to the dermatophyte fungi – causes of ringworm and athlete's foot. However, other types of

Antifungal agents and the future

This review has summarised all known types of clinically used antifungal agents, their molecular targets and modes of action. Over the 50 or more years in which specific antifungal agents have been discovered, the clinical needs for the agents have altered considerably and continuously. Superficial mycoses remain relatively easy to treat, with a large range of antimycotic products now available over the counter for the purpose. The spectrum of disseminated mycoses in highly immunocompromised

Acknowledgements

We thank the British Society for Antimicrobial Chemotherapy, the Wellcome Trust and the Biotechnology and Biological Sciences Research Council for supporting related aspects of our research.

References (31)

D.W. Denning
Sequencing the Aspergillus fumigatus genome
Lancet Infect. Dis.
(2002)
S.L. Kelly
Characterization of Saccharomyces cerevisiae cyp61, sterol Δ²²-desaturase, and inhibition by azole antifungal agents
J. Biol. Chem.
(1997)
L.M. Podust
Substrate recognition sites in 14α-sterol demethylase from comparative analysis of amino acid sequences and X-ray structure of Mycobacterium tuberculosis CYP51
J. Inorg. Biochem.
(2001)
D. Sanglard et al.
Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences
Lancet Infect. Dis.
(2002)
S. Scherer
Gene discovery and comparative genomics: progress and prospects
J.E. Schein
Physical maps for genome analysis of serotype A and D strains of the fungal pathogen Cryptococcus neoformans
Genome Res.
(2002)
A. Goffeau
The yeast genome directory
Nature
(1997)
M.D. De Backer
Functional genomics approaches for the identification and validation of antifungal drug targets
Am. J. Pharmacogenomics
(2002)
D.F. Horrobin
Realism in drug discovery – could Cassandra be right?
Nat. Biotechnol.
(2001)
F.C. Odds
Sordarin antifungal agents
Expert Opin. Ther. Pat.
(2001)

M.B. Edmond

Nosocomial bloodstream infections in United States hospitals: a three-year analysis

Clin. Infect. Dis.

(1999)

W.E. Trick

Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999

Clin. Infect. Dis.

(2002)

T. Yamazaki

Epidemiology of visceral mycoses: analysis of data in Annual of the Pathological Autopsy Cases in Japan

J. Clin. Microbiol.

(1999)

M. Develoux

Griseofulvin

Ann. Dermatol. Veneréol.

(2001)

T. Woyke

Effect of auristatin PHE on microtubule integrity and nuclear localization in Cryptococcus neoformans

Antimicrob. Agents Chemother.

(2002)

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Trends in Microbiology

Antifungal agents: mechanisms of action

Abstract

Section snippets

New targets, new agents and clinical realities

Griseofulvin

Antifungal agents and the future

Acknowledgements

Lancet Infect. Dis.

J. Biol. Chem.

J. Inorg. Biochem.

Lancet Infect. Dis.

Gene discovery and comparative genomics: progress and prospects

Physical maps for genome analysis of serotype A and D strains of the fungal pathogen Cryptococcus neoformans

Genome Res.

The yeast genome directory

Nature

Functional genomics approaches for the identification and validation of antifungal drug targets

Am. J. Pharmacogenomics

Realism in drug discovery – could Cassandra be right?

Nat. Biotechnol.

Sordarin antifungal agents

Expert Opin. Ther. Pat.

Nosocomial bloodstream infections in United States hospitals: a three-year analysis

Clin. Infect. Dis.

Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999

Clin. Infect. Dis.

Epidemiology of visceral mycoses: analysis of data in Annual of the Pathological Autopsy Cases in Japan

J. Clin. Microbiol.

Griseofulvin

Ann. Dermatol. Veneréol.

Effect of auristatin PHE on microtubule integrity and nuclear localization in Cryptococcus neoformans

Antimicrob. Agents Chemother.