Milbemycin A4 oxime as a probe of azole transport in<i>Candida glabrata</i>

Walker, Bryan A.; Izumikawa, Koichi; Tsai, Huie Fung; Bennett, John E.

doi:10.1111/1567-1364.12164

Cited by 6 publications

(4 citation statements)

References 19 publications

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“…The MICs of the short-tailed azoles fluconazole and voriconazole in isolate P3 are mostly attributed to MFS7 , a major facilitator that is upregulated in P3. Major facilitators are not inhibited by milbemycins [ 23 , 24 , 25 ], which, therefore, preserved the short-tailed azole MICs of isolate P3 even in the presence of AOx3.…”

Section: Resultsmentioning

confidence: 99%

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

Borgeat

Brandalise

Grenouillet

et al. 2021

JoF

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Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations.

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Section: Resultsmentioning

confidence: 99%

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

Borgeat

Brandalise

Grenouillet

et al. 2021

JoF

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“…As shown in Table 3, all isolates except strains of C. zemplinina and D. hansenii were capable of growing in apple juice at 37C (human body temperature), which might pose a threat to human health because strains belonging to C. orthopsilosis, C. glabrata and W. anomalus have been reported to be important opportunistic fungal pathogens (Blanco-Blanco et al 2014;de Oliveira et al 2014;Walker et al 2014). Lowering of the storage temperature down to 12C hardly affected the growth.…”

Section: Resultsmentioning

confidence: 99%

The Effects of Stress Factors on the Growth of Spoilage Yeasts Isolated From Apple‐Related Environments in Apple Juice

Wang

Long

et al. 2015

Journal of Food Safety

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This study aimed to evaluate the effects of temperature, pH, sugar content and antimicrobial components on the growth of 11 yeast isolates in apple juice (12°B rix, pH 4.0). The results showed that reduction of the storage temperature to 4C could achieve a complete inhibition of test strains, and the temperature required to kill all the initial yeast inoculum (10 3 cfu/mL) within 20 min ranged from 46 to 55C, depending on the isolate. However, high sugar content enabled test strains to survive in what would have been a lethal treatment. A pH value below 2.0 had a significant inhibitory effect on the growth of test strains. Increasing the sugar content of apple juice was not enough to completely avoid the spoilage caused by the test strains, especially Zygosaccharomyces rouxii. Addition of antimicrobial components (4.0 mM sorbic acid, 1.5 mM cinnamic acid, 20 mM vanillin, 10 mM ferulic acid or 12 mM p-coumaric acid) was an applicable strategy to prevent the spoilage in apple juice spawned by the test strains. PRACTICAL APPLICATIONSWith the rapid improvement of living standards, there has been a considerable increase in the demand for better quality apple juice. Quality deterioration is a frequently reported problem in apple juice industry, which mainly resulted from microbial contamination, especially osmotolerant yeasts, that alters the original flavor by the production of new odor-active metabolites. Therefore, development of effective strategy to prevent the spoilage is an important issue. Stress factors including temperature, pH, sugar content and antimicrobial components are all used to inhibit yeast species and other microorganisms in food. Study of the effects of these factors on the growth of yeasts is advantageous to extend the microbial stability of apple juice during storage. The results show that addition of antimicrobial components, applicable to apple juice industry, is sufficient to extend the shelf life of apple juice for more than 50 days.

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“…glabrata and C. albicans (16, 48, 49). Azole resistance could also be reduced with milbemycin oxime in Indian Trichophyton mentagrophytes strains recently sent for examination (data not shown), suggesting overexpression of the MDR3 ortholog in these fungi.…”

Section: Discussionmentioning

confidence: 99%