New Cell Wall-Affecting Antifungal Antibiotics

Abstract

Fungi have emerged worldwide as increasingly frequent causes of healthcareassociated infections. Invasive fungal infections can be life-threatening. However, the number of antifungal agents available and their use in therapy is very limited. Recently, a new family of specific fungal cell wall synthesis inhibitors has emerged as an alternative antifungal therapy and is gaining increasing relevance yearly. The cell wall is a multilayer dynamic structure, essential to the integrity and shape of the fungal cell, whose function is to counteract the osmotic forces that could otherwise produce fungal cell lysis. The cell wall is absent in nonfungal cells, therefore representing a useful target in discovering selective drugs for the treatment of fungal infections without causing toxicity in the host. Although fungi exhibit a considerable diversity in their cell wall structure, all present β(1,3)-, β(1,6)-and α(1,3)-glucans, chitin, and mannoproteins as their major cell wall components. Three different cell wall synthesis inhibitors of the lipopeptide family of echinocandins, named caspofungin, micafungin and anidulafungin, are commercially-available and new classes of cell wall synthesis inhibitors are emerging. This review provides an overview of what is so far known about the different classes of cell wall-affecting antifungal agents and their mechanism of action, offering new alternatives with clinical potential.

Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall

“…Moreover, analog 52a displayed potent antifungal activity against FLC-susceptible C. albicans ATCC 90028 (MIC 80 = 0.25 μg/mL), FLC-resistant C. albicans ATCC MYA-573 (MIC 80 = 0.25 μg/mL), C. glabrata (MIC 80 = 0.125 μg/mL), and C. tropicalis (MIC 80 = 0.063 μg/mL). Unfortunately, like GS synthetic inhibitors reported to date, these β-(1,6)- d -glucan synthesis inhibitors displayed little or no in vitro activity against C. neoformans . SARs revealed the nitrogen atom at the ring juncture was unessential for antifungal activity, whereas the nitrogen atom at the 3-position was indispensable for potent growth inhibition.…”

“…Unfortunately, like GS synthetic inhibitors reported to date, these β-(1,6)-D-glucan synthesis inhibitors displayed little or no in vitro activity against C. neoformans. 105 SARs revealed the nitrogen atom at the ring juncture was unessential for antifungal activity, whereas the nitrogen atom at the 3-position was indispensable for potent growth inhibition. The methyl group at the 5-position significantly enhanced antifungal efficacy compared to the 5-desmethyl analog.…”

The Cell Biology of Fission Yeast Septation

“…Although the extracellular matrix is not a rigid structure and does not provide osmotic support, it is considered the functional equivalent of the cell wall, and both structures are essential for the cell (2)(3)(4)(5). In addition, as in fungal cells, some extracellular matrix polymers are also important for cytokinesis (6)(7)(8)(9).…”