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Abstract
ABSTRACTThe plasma membrane H+-ATPase (Pma1) is an essential fungal protein and a proposed target for new antifungal medications. The compounds in a small-molecule library containing ∼191,000 commercially available compounds were screened for their ability to inhibit Saccharomyces cerevisiae plasma membranes containing Pma1. The overall hit rate was 0.2%, corresponding to 407 compounds. These hit compounds were further evaluated for ATPase selectivity and broad-spectrum antifungal activity. Following this work, one Pma1 inhibitor series based on compound 14 and analogs was selected for further evaluation. This compound series was able to depolarize the membrane and inhibit extracellular acidification in intact fungal cells concomitantly with a significant increase in intracellular ATP levels. Collectively, we suggest that these effects may be a common feature of Pma1 inhibitors. Additionally, the work uncovered a dual mechanism for the previously identified cationic peptide BM2, revealing fungal membrane disruption, in addition to Pma1 inhibition. The methods presented here provide a solid platform for the evaluation of Pma1-specific inhibitors in a drug development setting. The present inhibitors could serve as a starting point for the development of new antifungal agents with a novel mode of action.
Highlights
The plasma membrane Hϩ-ATPase (Pma1) is an essential fungal protein and a proposed target for new antifungal medications
Fungal cells are fundamentally different from human cells, where the plasma membrane potential is created by the Naϩ,Kϩ-ATPase [8]
All 407 hits were counterscreened for their activity against Naϩ,Kϩ-ATPase and sarcoplasmic endoplasmic reticulum Ca2ϩATPase (SERCA) in order to distinguish Pma1-specific compounds from general P-type ATPase inhibitors
Summary
The plasma membrane Hϩ-ATPase (Pma1) is an essential fungal protein and a proposed target for new antifungal medications. One Pma inhibitor series based on compound 14 and analogs was selected for further evaluation This compound series was able to depolarize the membrane and inhibit extracellular acidification in intact fungal cells concomitantly with a significant increase in intracellular ATP levels. Key areas of concern in the treatment of invasive fungal infections with the current antifungal medications include delays in diagnosis and the identification of the specific pathogenic species, intrinsic and acquired drug resistance, inconvenient drug administration, safety, and tolerability issues with prolonged use. For these reasons, there is a major unmet need for new antifungal agents [3]. The high level of conservation seen for Pma warrants efforts to identify a specific Pma inhibitor with broad-spectrum antifungal activity
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