Synergistic action of nikkomycin X/Z with azole antifungals on Candida albicans

Milewski, Sławomir; Mignini, Fiorenzo; Borowski, Edward

doi:10.1099/00221287-137-9-2155

Cited by 35 publications

(31 citation statements)

References 23 publications

(15 reference statements)

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“…The fungus, when exposed to combinations of these antifungal agents, may therefore be attacked on two fronts. Previous studies (4,6) by checkerboard titration have also indicated that nikkomycins (X and Z) in combination with azoles interact synergistically against C. albicans in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Improvements in the efficacy of antifungal drug therapy and reductions in toxicity may be achieved by using combinations of drugs. To date there have been few investigations of the interactions between antifungal agents (1,3,4,(6)(7)(8).One of the limitations to such studies on the evaluation of antifungal activity has been the lack of an adequate in vitro methodology capable of yielding reproducible results. Sanders et al (11) pointed out the inherent methodologic limitations of the two most widely used methods for assessing drug interactions, namely, the time-kill technique and the checkerboard titration, and went on to describe a new in vitro test for antibacterial agents designed to avoid many of the problems previously described (11).…”

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Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro

Tariq

Scott

McCain

1995

Antimicrob Agents Chemother

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Interactions between six compounds (econazole, miconazole, amphotericin B, nystatin, nikkomycin Z, and ibuprofen) were investigated for their antifungal activities against Candida albicans by using pair combinations in an in vitro decimal assay for additivity based on disk diffusion. Additive interactions were observed between miconazole and econazole, amphotericin B and nystatin, and amphotericin B and ibuprofen, while an antagonistic interaction was observed between econazole and amphotericin B. Synergistic interactions were recorded for the combinations of econazole and ibuprofen, econazole and nikkomycin Z, and ibuprofen and nikkomycin Z.Candida albicans is an opportunistic fungal pathogen responsible for causing candidiasis in individuals with an underlying pathological process or deficiency state. Increases in the numbers of immunocompromised individuals have resulted in concomitant increases in the occurrence of Candida infections (9). For more than two decades the fungicidal polyene compounds, such as amphotericin B and nystatin, provided the most effective treatment of candidiasis, despite their potential toxicity to humans. More recently, the azole antifungal compounds have emerged as the principal drugs used in the treatment of candidiasis, although their activities are fungistatic rather than fungicidal (2). Improvements in the efficacy of antifungal drug therapy and reductions in toxicity may be achieved by using combinations of drugs. To date there have been few investigations of the interactions between antifungal agents (1,3,4,(6)(7)(8).One of the limitations to such studies on the evaluation of antifungal activity has been the lack of an adequate in vitro methodology capable of yielding reproducible results. Sanders et al. (11) pointed out the inherent methodologic limitations of the two most widely used methods for assessing drug interactions, namely, the time-kill technique and the checkerboard titration, and went on to describe a new in vitro test for antibacterial agents designed to avoid many of the problems previously described (11). This new test, the decimal assay for additivity (DAA), was based on the disk diffusion assay and was designed to have a precisely defined endpoint for additivity so that interactions greater or less than additivity (i.e., synergism or antagonism, respectively) could be accurately identified. The DAA involves initially performing disk diffusion assays with each antibiotic on its own over a range of drug masses in order to obtain a standard dose-response curve. A target zone of inhibition for each drug combination, representing a zone in the midrange of the standard curve for each drug, is selected so that increases or decreases in zones of inhibition resulting from drug interactions can be reliably detected. The mass of each drug on its own required to produce this target zone (i.e., the biologic equivalence factor [BEF]) is calculated by using the linear regression equation for the standard doseresponse curve. Once the two BEFs for a combination of a pair of d...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro

Tariq

Scott

McCain

1995

Antimicrob Agents Chemother

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“…The first possibility, of increased hydrolysis of the peptide in the presence of certain amino acids, may be ruled out since amino acids increase sensitivity of C. albicans to both oxalysinecontaining peptides and nikkomycin X + Z (Table 6). The peptidyl nucleoside nikkomycin X + Z inhibits chitin synthase activity in an intact form and is resistant to peptidase cleavage Decker et al, 1991 ;Krainer et al, 1991 ;Milewski et al, 1991 b). The second possibility, of alteration of intracellular target by certain amino acids, is unlikely based on the different targets of action of the two anticandidal agents; nikkomycin inhibits chitin synthase whereas oxalysine inhibits RNA synthesis (Zheng et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Toxicity of oxalysine and oxalysine-containing peptides against Candida albicans: regulation of peptide transport by amino acids

Basrai

Zhang

Miller

et al. 1992

Journal of General Microbiology

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A lysine antimetabolite, L-4-oxalysine [ H2NCH2CH20CH2CH(NH2)COOH], and oxalysine-containing di-, tri-, tetra-and pentapeptides inhibited growth of Candidu albicans H317. Micromolar amounts of amino acids were found to overcome ammonium repression of the di-and tripeptide transport system(s) in strain H317. Several amino acids increased the toxicity of oxalysine-containing di-and tripeptides for C. albicans with little or no increase in toxicity of oxalysine or oxalysine-containing tetra-and pentapeptides. L-Lysine completely reversed the toxicity of oxalysine by competing with the transport of oxalysine into the cells. In contrast, L-lysine increased the toxicity of oxalysine-containing di-and tripeptides, but had no effect on the toxicity of oxalysine-containing tetra-and pentapeptides. Incubation of cells with L-lysine for 4 h resulted in a 15-fold increase in the rate of transport of radiolabelled dileucine, indicating that increased sensitivity of C. ufbicans to some toxic peptides in the presence of L-lysine may be attributed to an increased rate of transport of these peptides. Our results indicate that the dipeptide and tripeptide transport system(s) of C. ulbicuns are regulated by micromolar amounts of amino acids in a similar fashion to the regulation of peptide transport in Succhuromyces cerevisiue and that multiple peptide transport systems differentially regulated by various nitrogen sources and amino acids exist in C. ulbicuns.

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“…Other recent reports describe the synergistic interaction of combinations of nikkomycin and azole antifungal agents against C. albicans in vitro and in vivo (110,162). This phenomenon is probably a result of the previously described secondary effects of azoles on chitin synthesis (107,188,255) being compounded by the specific inhibition of this polymer by nikkomycin.…”

Section: Combinations Of Cell Wall-active Substancesmentioning

confidence: 89%

Compounds active against cell walls of medically important fungi

Hector

1993

Clin Microbiol Rev

215

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A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

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Synergistic action of nikkomycin X/Z with azole antifungals on Candida albicans

Cited by 35 publications

References 23 publications

Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro

Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro

Toxicity of oxalysine and oxalysine-containing peptides against Candida albicans: regulation of peptide transport by amino acids

Compounds active against cell walls of medically important fungi

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