Fungal persister cells: The basis for recalcitrant infections?

Abstract

Persister cells are a small subpopulation within fungal biofilms that are highly resistant to high concentrations of antifungals and therefore most likely contribute to the resistance and recalcitrance of biofilm infections. Moreover, this subpopulation is defined as a nongrowing, phenotypic variant of wild-type cells that can survive high doses of antifungals. There are high degrees of heterogeneity and plasticity associated with biofilm formation, resulting in a strong variation in the amount of persister cells. The fraction of these cells in fungal biofilms also appear to be dependent on the type of substrate. The cells can be observed immediately after their adhesion to that substrate, which makes up the initial step of biofilm formation. Thus far, persister cells have primarily been studied in Candida spp. These fungi are the fourth most common cause of nosocomial systemic infections in the United States, with C. albicans being the most prevalent species. Remarkably, persisters exhibit characteristics of a dormant state similar to what is observed in cells deprived of glucose. This dormant state, together with attachment to a substrate, appears to provide the cells with characteristics that help them overcome the challenges with fungicidal drugs such as amphotericin B (AmB). AmB is known to induce apoptosis, and persister cells are able to cope with the increase in reactive oxygen species (ROS) by activating stress response pathways and the accumulation of high amounts of glycogen and trehalose—two known stress-protecting molecules. In this review, we discuss the molecular pathways that are involved in persister cell formation in fungal species and highlight that the eradication of persister cells could lead to a strong reduction of treatment failure in a clinical setting.

Power-law tail in lag time distribution underlies bacterial persistence

“…Therefore, our observation of a power-law decay in rejuvenation probability further highlights the need to develop new interventions to rejuvenate persister cells [as was previously demonstrated (64)] or new antibiotics that can directly target persister cells (65). Importantly, persistence is a general phenomenon as it has been observed not only for bacteria but also for fungi and mammalian cells (66)(67)(68). It would be interesting to investigate the generality of our findings.…”

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…Life-threatening invasive candidiasis and invasive aspergillosis are among the most common healthcare-associated infections (HAIs), requiring longer hospitalization stay and often expensive antifungal drugs, thus contributing to increased healthcare costs [7,9,10]. Candida bloodstream infections, which have mortality rates around 50%, are HAIs frequently related with the use of central venous catheters (CVCs) and treatment often requires catheter removal due to formation of recalcitrant biofilms [10][11][12].…”

“…Biofilm formation, an important virulence factor for pathogenic fungi, often contributes to the development of antimicrobial resistance [11][12][13][14]. Fungal biofilms are surface-associated communities of microbial cells protected by an extracellular polysaccharide-rich matrix that inhibits diffusion and cell uptake of antimicrobial agents [11,12,15]. Decreased susceptibility to antifungal drugs results in higher minimum inhibitory concentration (MIC) values for microbial strains grown as biofilms compared to their corresponding planktonic forms [15].…”

Eradication of Candida albicans persister cell biofilm by the membranotropic peptide gH625

“…Persister cells present a particular case of tolerance (able to survive a transient exposure to antibiotics) and constitute a subpopulation (on average less than 1%) that is killed at a slower rate than susceptible cells 8 . Persisters have been initially detected in mature biofilms of C. albicans 9 and then in several other Candida spp 10 .…”