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Review
. 2024;19(7):621-630.
doi: 10.2217/fmb-2023-0236. Epub 2024 Mar 18.

Rise and fall of Caspofungin: the current status of Caspofungin as a treatment for Cryptococcus neoformans infection

Tawanny Kb Aguiar  1 , Ana Cm Costa  1 , Nilton As Neto  2 , Daiane Ms Brito  1   3 , Cleverson Dt Freitas  1 , João Mm Neto  1 , Felipe P Mesquita  3 , Pedro Fn Souza  3
Affiliations
Review

Rise and fall of Caspofungin: the current status of Caspofungin as a treatment for Cryptococcus neoformans infection

Tawanny Kb Aguiar et al. Future Microbiol. 2024.

Abstract

Antifungal infections are becoming a major concern to human health due to antimicrobial resistance. Echinocandins have been promising agents against resistant fungal infections, primarily caspofungin, which has a more effective mechanism of action than azoles and polyenes. However, fungi such as Cryptococcus neoformans appear to be inheritably resistant to these drugs, which is concerning due to the high clinical importance of C. neoformans. In this review, we review the history of C. neoformans and the treatments used to treat antifungals over the years, focusing on caspofungin, while highlighting the C. neoformans problem and possible explanations for its inherent resistance.

Keywords: Cryptococcus neoformans; echinocandins; glucan synthesis; resistance.

Plain language summary

Caspofungin is a drug used to treat several types of fungal infections. Resistance to caspofungin is a huge problem, especially in those that are immunocompromised. It is important to understand the history of caspofungin discovery, its clinical applications and its mechanism of action, as well as if a new drug target could be used overcome resistance. This review may perform guide new studies combining caspofungin with other drugs and indicate new potential targets for caspofungin.

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Conflict of interest statement

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1.
Figure 1.
Mechanisms of resistance of C. neoformans to caspofungin. Efflux pumps decrease the intracellular concentration of the drug, avoiding inhibiting the FKS complex in the membrane. Cdc50 and puf4 ensure membrane and cell wall stability. Mutants of these genes result in cells sensitive to the action of caspofungin. The increase in genes involved in the synthesis of chitin and chitosan during treatment with caspofungin is related to a strengthened cell wall and strains resistant to the action of the drug. The synthesis of ergosterol also ensures the resistance of C. neoformans. Mutant strains of the ERG4 gene have their drug susceptibility rescued.
Figure 2.
Figure 2.
Comparison between HDAC4 from H. sapiens and C. neoformans. (A) Comparison of the amino acid sequence of HDAC4 from H. sapiens and C. neoformans using the alignment tool ESPript 3.0 (https://espript.ibcp.fr/ESPript/ESPript/). (B) 3D structure of HDAC4 from C. neoformans. (C) 3D structure of HDAC4 from H. sapiens. (D) 3D structural alignment between HDAC4 from H. sapiens (orange) and C. neoformans (green).
Figure 3.
Figure 3.
Molecular docking analysis of the interaction between caspofungin and HDAC4 from H. sapiens. (A) 3D image of caspofungin interaction with HDAC4 from H. sapiens analyzed by Pymol software. (B) A 2D map presenting hydrophobic/apolar interactions produced by LigPlot software. (C) 3D figures representing the interactions between HDAC4 and caspofungin produced by discovery.
Figure 4.
Figure 4.
Molecular docking analysis of the interaction between caspofungin and Q5KL48 from C. neoformans. (A) 3D image of caspofungin interaction with Q5KL48 from C. neoformans analyzed by Pymol software. (B) A 2D map presenting hydrophobic/apolar interactions produced by LigPlot software. (C) 3D figures representing the interactions between HDAC4 and caspofungin produced by Discovery.
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