DSP have 3 catalytic motifs, a shallow catalytic site to accommodate phosphotyrosine, phosphoserine and phosphothreonine. PTP include tyrosine-specific (sPTP), low molecular weight PTP (LMWPTP) and dual-specificity phosphatases (DSP) capable of dephosphorylating Tyr, Ser and Thr. Structural and sequence differences in the catalytic loop govern substrate specificity and enzyme function. Tyrosine phosphatases have evolved in structurally and functionally diverse families, are more numerous, less conserved and with lower substrate specificity than their cognate kinases. Phosphatases important in fungal growth and pathogenicity comprise the major Ser/Thr phosphatases, and cysteine-based tyrosine phosphatases (PTP) which share an essential cysteine catalytic motif. Fungal MAP kinases are generally highly conserved but show considerable functional divergence in number of MAPK genes and in activation loop motifs. The Mpk1 ‘cell wall integrity’ pathway, the ‘high osmolality glycerol’ (Hog1) stress response pathway and the Fus3/Kss1 mating and filamentation pathways, independently and cooperatively, play essential roles in fungal growth, development, virulence and adaptation to stress.
MAPK can be negatively regulated by serine, threonine and tyrosine phosphatases and dual specificity MAPK-specific phosphatases (MAPKP) that dephosphorylate either or both PTyr and PThr catalytic residues. The module ‘MAPK’ activates downstream kinases, phosphatases and tyrosine phosphoproteins (PTyr), resulting in the required signal responses. The ‘effector’ kinase in the ‘MAPK’ module, is a dual specificity Tyr/Thr kinase, activated by phosphorylation on catalytic Tyr and Thr residues by an upstream STK MAP kinase. MAP kinases are highly conserved signaling molecules that act in modules which share components, enabling pathway interactions. NPBD is a selective antifungal agent with low oral toxicity which would be suitable for local treatment of skin and mucosal infections. The activity profile of NPBD illustrates the functional diversity of fungal tyrosine phosphatases and thiol-based redox active molecules and contributes to the validation of tyrosine phosphatases and redox thiol molecules as related and complementary selective targets for antimicrobial drug development. A comparison of the metabolic activities of Amphotericin B, Miconazole and NPBD highlights the multiple cellular functions of these agents and the complementarity of many mechanisms. A literature review highlights the complexity and interactivity of fungal tyrosine phosphate and redox signaling pathways, their differing metabolic effects in fungal species and identifies some targets for inhibition. It did not induce resistant or drug tolerant strains in major pathogens on long term exposure. NPBD showed differing patterns of dynamic kill rates under different growth conditions for Candida albicans and Aspergillus fumigatus and was rapidly fungicidal for non-replicating vegetative forms and microconidia. NPBD was fungicidal to all species except the dermatophytic fungi, with an activity profile comparable to that of Amphotericin B and Miconazole. Nitropropenyl benzodioxole (NPBD), one of the most active antimicrobial derivatives, shows high activity in MIC assays for phylogenetically diverse saprophytic, commensal and parasitic fungi. Nitroalkenyl benzene derivatives are thiol oxidants and inhibitors of cysteine-based molecules, which show broad biological activity against microorganisms. Identification of new targets and development of new fungicidal drugs are required to augment the effectiveness of current chemotherapy and counter increasing resistance in pathogens. Phylogenetically diverse fungal species are an increasing cause of severe disease and mortality.
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