Physiological Properties Of Mutagen-Induced Variants Of Candida Albicans Resistant To Polyene Antibiotics

Hamilton‐Miller, J. M. T.

doi:10.1099/00222615-5-4-425

Cited by 29 publications

(9 citation statements)

References 17 publications

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“…Most of our knowledge of the mechanisms of resistance to polyenes in fungal species has come from studies using mutants generated by (i) growing cells in the presence of increasing concentrations of antifungal agents (multistep mutants), (ii) exposing the cells to a gradient concentration (4), or (iii) creating mutants by one-step mutation with mutagenic agents (45). Hamilton-Miller (46) proposed a "biochemical" hypothesis that resistance arises due to changes, either quantitative or qualitative, in the sterol content of the cells.…”

Section: Antimicrobial Agents Affecting Fungal Sterolsmentioning

confidence: 99%

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

1999

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SUMMARY The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

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Section: Antimicrobial Agents Affecting Fungal Sterolsmentioning

confidence: 99%

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

1999

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“…Different strains of C. albicans exhibit different susceptibilities to the commonly used antifungal drugs, including the polyenes (6, 27), 5-fluorocytosine (97, 123), and the azoles (46,50,92). There are, no doubt, a number of ways in which C. albicans achieves drug resistance, including mutation (43,47) and mitotic recombination (130). High-frequency switching can now be added to this list of mechanisms.…”

Section: Drug Susceptibilitymentioning

confidence: 99%

High-frequency switching in Candida albicans

1992

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Most strains of Candida albicans are capable of switching frequently and reversibly between a number of phenotypes distinguishable by colony morphology. A number of different switching systems have been defined according to the limited set of phenotypes in each switching repertoire, and each strain appears to possess a single system. Switching can affect many aspects of cellular physiology and morphology and appears to be a second level of phenotypic variability superimposed upon the bud-hypha transition. The most dramatic switching system so far identified is the "white-opaque transition." This system dramatizes the extraordinary effects switching can have on the budding cell phenotype, including the synthesis of opaque-specific antigens, the expression of white-specific and opaque-specific genes, and the genesis of unique cell wall structures. Switching has been demonstrated to occur at sites of infection and between episodes of recurrent vaginitis, and it may function to generate variability in commensal and infecting populations for adaptive reasons. Although the molecular mechanisms involved in the switch event are not understood, recent approaches to its elucidation are discussed and an epigenetic mechanism is proposed.

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“…Such primary resistance to 5-FC has been seen in varying degrees with a relatively wide range of clinical isolates of various fungus species. With Candida spp., a number of reports were published from 1971 to 1982 (8, 13, 16,34,36,41,42,50,59,64,68,69,93,107,115,132,138,151,152,154,156,164,165,173,175,176). In those reports, the highest levels in the incidence of resistant isolates of C. albicans recorded so far were 37.2% found among 175 strains in Canada (93), and 25.8% found in the study of 58 isolates in the United States (175); intermediate levels, e.g.…”

Section: Flucytosine Resistancementioning

confidence: 99%

“…With few exceptions, little or no cross-resistance of 5-FC-resistant strains has been experienced with any other antifungals (69,80,85,107). Contrariwise, Woods et aL (188) reported that an isolate of C. tropicalis, resistant to amphotericin B, was normally sensitive to 5-FG.…”

Section: Flucytosine Resistancementioning

confidence: 99%

Drug resistance in human pathogenic fungi

Iwata

1992

Eur J Epidemiol

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Since the therapy of the mycoses, particularly the systemic mycoses, is relatively long-term in nature, emergence of resistance to antifungal drugs during the treatment of period would be of considerable clinical importance. However, most reports of resistance to antifungal agents among human pathogenic fungi indicate that naturally-occurring resistance is very rare, and that the induction of resistant mutants or variants is much more difficult to achieve in vitro and in vivo than with bacteria. As a matter of fact, amphotericin B and some other classic antifungals have not as yet posed a broadly significant problem relative to drug resistance despite their widespread and frequent use. Fungal resistance has thus received little attention, in contrast to the critical importance of bacterial resistance frequently caused by a variety of antibacterial chemotherapeutic agents, until a single exception to this generalization arose with the advent of flucytosine. This new development has aroused great interest in the problem of fungal resistance among the scientists involved with medical mycology. It is generally believed that fungi, like bacteria, are intrinsically capable of developing resistance to antifungal agents. As illustrated by flucytosine, inherently resistant mutants to antifungals occur within sensitive strains of human pathogenic fungi with significant frequency. Given the relatively high degree of such primary resistance, these mutants should develop secondary resistance during therapy, thus resulting in considerable limitations in the clinical usefulness of the antifungals. Virtually, all unsuccessful cases of mycoses treated with some of the recently exploited antifungal drugs, albeit scarce to date, would obviously be attributable to the occurrence of secondary resistance. The exploitation of new antifungal drugs thus requires investigations of their resistance as one of the most important research projects to be undertaken before receiving approval for use on humans. This paper reviews from various aspects the literature on resistance to various classic and novel antifungal agents among human pathogenic fungi. The resistance of some nonpathogenic fungi to these agents will also be described from genetic and biochemical points of view.

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Physiological Properties Of Mutagen-Induced Variants Of Candida Albicans Resistant To Polyene Antibiotics

Cited by 29 publications

References 17 publications

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

High-frequency switching in Candida albicans

Drug resistance in human pathogenic fungi

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