The cAMP Signal Transduction Pathway Mediates Resistance to Dicarboximide and Aromatic Hydrocarbon Fungicides in Ustilago maydis

Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors

“…Here we examined a third conserved pathway that, similarly, is membrane associated: adenylate cyclase via the farnesylated-palmitoylated Ras proteins and CAP protein via the actin cytoskeleton (6,19). The cAMP-PKA pathway was previously implicated in fungal resistance to the antibiotic polymyxin B (4), dicarboximide, aromatic hydrocarbon fungicides (27,30) and, most pertinent to our studies here, fluconazole (21). It is not surprising that multiple mechanisms for responding to cell surface stress have evolved in unicellular organisms.…”

“…The cAMP-PKA pathway has been implicated in virulence, morphogenesis, and development in various fungi (1,10). More relevant to this work, it has been implicated in dicarboximide and aromatic hydrocarbon fungicide resistance in the phytopathogen Ustilago maydis (27,30) and polymixin B and fluconazole resistance in S. cerevisiae (4,21).…”

Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans

“…In N. crassa, a cAMP-and calcium-independent protein kinase is inhibited by phenylpyrroles, including fludioxonil (Pillonel & Mayer, 1997). On the other hand, in Ustilago maydis, mutants lacking cAMP-dependent protein kinase A (PKA) exhibit increased resistance to dicarboximide fungicides, although these fungicides do not directly inhibit PKA (Orth et al, 1995;Ramesh et al, 2001). Interestingly, a Colletotrichum lagenarium mutant lacking the PKA regulatory subunit shows significantly increased sensitivity to fludioxonil (Kojima et al, 2004).…”

Detection of Fungicide Resistance

“…The first molecular mechanism of dicarboximide resistance was identified in U. maydis (Orth et al 1994), and is one of the few instances where the gene was found to be sufficient for conferring resistance to a wild-type isolate via transformation (Orth et al 1995). The gene, termed adr1, is a 1,218 bp open reading frame with homology to serine/threonine protein kinases that was later identified as the major cAMP dependent protein kinase; However, later studies by Ramesh et al (2001), found that the adr1-encoded enzyme was not the direct target of vinclozolin inhibition but that mutants with a defect in the regulatory subunit of cAMP-dependent protein kinase (ubc1) exhibited resistance to vinclozolin and the aromatic hydrocarbon, chloroneb. Mutants with a defect in the ubc1 gene also display interesting changes in morphology, including a reduction in multiple budding in the presence of the fungicides and osmotic sensitivity, suggesting a connection between fungicide mode of action and morphogenesis and glycerol accumulation (which would also be related to osmotic, turgor regulation and osmotic shock), which may explain why this mutation has never been reported from field isolates with fungicide resistance phenotypes (Ramesh et al 2001).…”