Introduction

Invasive fungal infections pose a significant threat to global health, particularly among immunocompromised individuals. The past five years have witnessed a surge in research focused on understanding and combating antifungal resistance, driven by the emergence of multidrug-resistant strains and the limited arsenal of available antifungal agents. This mini-review synthesizes recent advancements in this field, focusing on the mechanisms of resistance, the rise of Candida auris, and novel therapeutic strategies.

Mechanisms of Antifungal Resistance and Virulence

A significant body of research has focused on elucidating the mechanisms underlying antifungal resistance. Neil A. R. Gow's group has consistently highlighted the importance of antimicrobial resistance in medical mycology, emphasizing its growing clinical relevance (Neil A. R. Gow et al., 2020, Nature Communications; Neil A. R. Gow et al., 2021, Nature Communications; Neil A. R. Gow et al., 2022, Nature Communications). Studies have investigated specific resistance mechanisms in various fungal species. For example, Michael J. Bromley's laboratory identified the negative cofactor 2 complex as a key regulator of drug resistance in Aspergillus fumigatus (Takanori Furukawa et al., 2020, Nature Communications). Furthermore, Toni Gabaldón's research group has shown that narrow mutational signatures drive the acquisition of multidrug resistance in Candida glabrata (Ewa Księżopolska et al., 2021, Current Biology). More recently, Toni Gabaldón's group has also shown that recent gene selection and drug resistance underscore clinical adaptation across Candida species (Miquel Àngel Schikora-Tamarit et al., 2024, Nature Microbiology).

Biofilm formation has also emerged as a critical factor in antifungal resistance. Robert A. Cramer's group demonstrated that fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance (Caitlin H. Kowalski et al., 2020, Proceedings of the National Academy of Sciences). Clarissa J. Nobile's laboratory has provided comprehensive reviews of antifungal drug-resistance mechanisms in Candida biofilms, highlighting the complex interplay between biofilm structure and drug susceptibility (Jaspreet Kaur et al., 2021, Current Opinion in Microbiology; Jaspreet Kaur et al., 2022, Current Opinion in Microbiology). Rebecca S. Shapiro's group has also contributed to the understanding of stress tolerance and biofilm formation in Nakaseomyces (Candida) glabrata using a novel CRISPR activation system (Laetitia Maroc et al., 2024, MSphere).

The role of macrophages in promoting drug resistance has also been investigated. David S. Perlin's laboratory has shown that macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance (Amir Arastehfar et al., 2023, Nature Communications).

The Rise of Candida auris and its Unique Challenges

The emergence and rapid spread of Candida auris has been a major focus of research. Anuradha Chowdhary's group has extensively studied the genetics and emergence of C. auris, providing valuable insights into its evolutionary history and mechanisms of adaptation (Anuradha Chowdhary et al., 2022, Annual Review of Microbiology; Anuradha Chowdhary et al., 2023, Annual Review of Microbiology). Suhail Ahmad's laboratory has provided comprehensive overviews of the epidemiology, diagnosis, pathogenesis, and antifungal susceptibility of C. auris (Suhail Ahmad et al., 2020, Microorganisms; Suhail Ahmad et al., 2021, Microorganisms). Jennifer Chan's group has also contributed to the understanding of this emerging threat with an overview of the drug-resistant fungal infection (Adekunle Sanyaolu et al., 2021, Infection and Chemotherapy; Adekunle Sanyaolu et al., 2022, Infection and Chemotherapy).

Research has also explored the mechanisms of resistance in C. auris. Anuradha Chowdhary's group has used comparative transcriptomics to reveal possible mechanisms of amphotericin B resistance in C. auris (Raju Shivarathri et al., 2022, Antimicrobial Agents and Chemotherapy). Hans Carolus's and Patrick Van Dijck's groups have shown that acquired amphotericin B resistance leads to fitness trade-offs that can be mitigated by compensatory evolution in Candida auris (Hans Carolus et al., 2024, Nature Microbiology). Linqi Wang's laboratory has found that pan-drug resistance and hypervirulence in a human fungal pathogen are enabled by mutagenesis induced by mammalian body temperature (Jingjing Huang et al., 2024, Nature Microbiology).

Novel Therapeutic Strategies and Drug Development

Faced with increasing antifungal resistance, researchers have been actively exploring novel therapeutic strategies. Martin Hoenigl's group has provided updates on the antifungal pipeline, highlighting promising new agents such as fosmanogepix, ibrexafungerp, olorofim, opelconazole, and rezafungin (Martin Hoenigl et al., 2020, Drugs; Martin Hoenigl et al., 2021, Drugs). Runhui Liu's laboratory has developed short guanidinium-functionalized poly(2-oxazoline)s displaying potent therapeutic efficacy on drug-resistant fungal infections (Weinan Jiang et al., 2022, Angewandte Chemie International Edition) and a dual-targeting antifungal that is effective against multidrug-resistant human fungal pathogens (Min Zhou et al., 2024, Nature Microbiology). Leah E. Cowen's group has identified imidazopyrazoindoles that target fungal membrane homeostasis, impairing azole resistance and biofilm formation (Nicole M. Revie et al., 2021, Nature Communications; Nicole M. Revie et al., 2022, Nature Communications). Gustavo H. Goldman's laboratory has shown that a host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi (Thaila Fernanda dos Reis et al., 2023, Nature Communications). Mohamed N. Seleem's group has found that saquinavir potentiates itraconazole’s antifungal activity against multidrug-resistant Candida auris in vitro and in vivo (Yehia Elgammal et al., 2023, Medical Mycology) and that lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris (Ehab A. Salama et al., 2024, Emerg. microbes & infect.). Iuliana V. Ene's laboratory has identified small molecules that restore azole activity against drug-tolerant and drug-resistant Candida isolates (Philip Alabi et al., 2023, mBio). Elaine Bignell's group has demonstrated the heightened efficacy of anidulafungin when used in combination with manogepix or 5-flucytosine against Candida auris In Vitro (Larissa L.H. John et al., 2023, Antimicrobial Agents and Chemotherapy). Robert A. Cramer's laboratory has shown that unsaturated fatty acid perturbation combats emerging triazole antifungal resistance in the human fungal pathogen Aspergillus fumigatus (Cecilia Gutierrez-Perez et al., 2024, mBio).

Conclusion

The past five years have seen significant progress in understanding the mechanisms of antifungal resistance and in developing novel therapeutic strategies. The emergence of Candida auris has spurred intense research efforts, leading to a better understanding of its unique characteristics and vulnerabilities. While challenges remain, the ongoing research provides hope for improved prevention and treatment of invasive fungal infections in the future.

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