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

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,*
PMCID: PMC11229582  PMID: 38497911

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.

Plain language summary

Executive summary.

Resistance to caspofungin

  • Caspofungin arose as a new potential drug against fungi; however, the intrinsic resistance of some fungi shadowed its potential.

Synergism as an option to overcome resistance to caspofungin

  • The combination with some antimicrobial peptides could help to bring back the effectiveness of caspofungin.

Application of bioinformatics

  • Bioinformatics helped to find a new potential intracellular target for caspofungin.

New targets for caspofungin

  • HDCA4 is a candidate for a new target of caspofungin once within the cell.

Future perspective

  • Understanding the resistance of C. neoformans to caspofungin will help to overcome this problem.

The exponential increase in systemic infections caused by multidrug-resistant fungal pathogens has resulted in a growing worldwide concern. The development of new antifungal drugs has not been able to keep up with the clinical need [1]. For example, cryptococcal meningitis treatment uses amphotericin B in combination with flucytosine, followed by consolidation monotherapy with fluconazole but, because fluconazole is fungistatic, prolonged exposure to the drug results in the adaptation of cryptococcal populations to the endure the stress and become resistant to the drug [2,3]. In addition, the toxicity of both drugs is high. More therapeutic options are therefore needed for better management of advanced cryptococcosis [4].

Echinocandins have emerged as a promising class of antifungal drugs. However, C. neoformans has shown that it is not sensitive to echinocandin activity, with inherent resistance [5]. Still, for most common fungal infections, echinocandins and azoles are the first line of treatment [1]. Rezafungin, a new antifungal from the echinocandin class, has a long half-life, shown a quick recovery for stable patients and can be used as a prophylactic in immunocompromised patients [6]. The drug was released in March 2023 by the USA for use in patients ≥18 years to treat serious infections caused by Candida species [7]. Despite this, rezafungin and other drugs of the same class have not shown satisfactory results against C. neoformans [8].

To circumvent the action of different antifungals, microorganisms have developed multiple pathways to resistance: 1) reducing the intracellular concentration of the drug through efflux pumps, 2) biochemical alteration in the drug target, and 3) alterations in metabolism to avoid the toxic effects of the drug [9]. These mechanisms have been observed in the resistance of C. neoformans to drugs that interact with membrane ergosterol or inhibit its synthesis. However, the innate resistance of C. neoformans to echinocandins is poorly understood. Therefore, this review discusses the mechanisms already described to explain the resistance to echinocandins of the fungal pathogen C. neoformans.

Antifungals & Cryptococcus neoformans

To treat fungal diseases in general, a clinician's arsenal consists of the azoles, echinocandins, polyenes and pyrimidine analogs. For the treatment of cryptococcal meningitis, the World Health Organization (WHO) guidelines recommend a single dose of liposomal amphotericin B combined with drugs such as flucytosine and fluconazole [10].

The mechanism of action of azoles consists of the inhibition of 14 α-demethylase, a crucial enzyme in the process of ergosterol synthesis, responsible for its conversion from lanosterol [11]. The presence of efflux pumps is common in cases of antifungal resistance. Due to their role, these pumps decrease the intracellular concentrations of the drugs. For example, a class of efflux pumps, ABC transporter, is overexpressed in C. neoformans cells, which usually accumulate during the chronic stage of infection [10]. Exposure to pesticides from the azoles class widely used in agriculture contributes to the emergence of resistance to azole-class drugs, such as fluconazole [1].

A study with a clinical isolate resistant to high concentrations of fluconazole showed the importance of alterations in the ERG11 gene in C. neoformans [2]. In this case, a single mutation that substituted tyrosine for phenylalanine produced fluconazole resistance in the strain. This shows that small alterations in the gene that encodes the catalytic subunit of lanosterol 14 α-demethylase can decrease the affinity of azole drugs for the enzyme and promote the resistance of these microorganisms [2].

The polyenes' mode of action differs from the other classes because of the high affinity for the ergosterol in the fungal membrane, binding and thus promoting cell lysis [12,13]. The mechanisms of resistance to polyenes are not yet well understood in Cryptococcus species. One of the first mechanisms proposed suggested mutations in the sterol 8–7 isomerase gene involved in ergosterol biosynthesis [14]. Later, an in vitro study demonstrated that resistance to amphotericin B could also be developed without relation to the ergosterol content in the fungus [15]. However, the common mechanism of resistance to polyenes, even in other fungal species, is the alteration of the composition or sterol content in the fungal membrane [16].

Flucytosine (FLC), which interferes with the synthesis of fungal nucleic acids, is usually used in combination with another antifungal because monotherapies are associated with rapid acquisition of resistance [17,18]. FLC seemed like the ideal medicine when it was released for use because its target is absent in human cells. The recommended dosage of FLC for the treatment of adults and children is for adults and children is 150–200 mg/kg [3]. However, when administered in concentrations above 100 mg/l, patients show symptoms of bone marrow depression and hepatotoxicity [19,20]. Two mechanisms have been proposed to explain flucytosine resistance. The first suggests that enzyme deficiency related to drug transport or metabolism would be responsible for resistance. The second proposes that resistance results from increased synthesis of pyrimidines that compete with flucytosine antimetabolites [21].

Enzymes involved in synthesizing fungal cell wall components are promising targets for new drugs. However, few classes of cell wall inhibitors have been successfully developed for clinical use [5]. The last class of antifungals released for use was echinocandins. The mode of action consists of inhibiting the synthesis of 1,3-β-glucans non-competitively [22]. Inhibition of β-1,3-glucan synthase enzyme activity results in cell lysis due to osmotic instability [23]. Resistance of Candida species to echinocandin is most related to mutations in two conserved regions of the FKS1 gene [4]. FKS1 and FKS2 are the genes that encode the enzyme β-1,3-glucan synthase, which is the target of echinocandins [24].

A brief history of caspofungin

The echinocandins differ from each other due to their side chains. Still, three characteristics are essential and common among them: 1) a homotyrosine amino acid residue, 2) proline residue, and 3) hydroxyl groups located at the core of their structures [4]. Caspofungin – the main medicine of the class – was the first agent approved and available for the treatment of fungal infections [25]. Before that, fungal diseases were treated with azoles, flucytosine, and polyenes. However, the growing number of species resistant to antifungals that bind to ergosterol (polyenes) or block its synthesis (azoles), brought raised concerns about the use of these drugs [26].

Treatment with caspofungin generally has fewer adverse effects than polyene drugs [27]. In infections caused by Candida species, echinocandins are the first line of treatment [28]. However, in recent years, cases of resistant Candida species have increased [29]. Echinocandins are administered intravenously, and resistance can occur during treatment, where resistant isolates spread in hospitals, causing concern [30]. Today, no direct connection exists between intravenous administration and resistance was discussed in the literature. However, many factors, such as the patient's weak immune system, could help the clinical resistance. Clinical resistance is the failure of a drug to eradicate the infection from the patient. The most important reason for the resistance, in the case of caspofungin, is the intrinsic resistance of C. neoformans to it.

Caspofungin has been cleared for use by the Food and Drug Administration (US FDA) to treat infections caused by Candida and for cases of suspected invasive fungal infections [31]. It is a water-soluble semi-synthetic lipopeptide produced from a fermentation product of the fungus Glarea lozoyensis [6]. Caspofungin approved in 2001, micafungin approved in 2005, and anidulafungin approved in 2006 are the first generation of echinocandins, and each approved for once-a-day intravenous administration [32].

The fact that the caspofungin target is completely absent in the human body has made it an ideal treatment for invasive infections [5]. Caspofungin's mechanism of action produces a fungistatic and fungicidal effect. The fungistatic effect occurs by blocking the cell wall synthesis. The fungicidal effect results from the alteration in the integrity of the cell wall, making the cell's life unviable [6].

In the first years of using caspofungin on the market, the first studies already related mutations in the genes that codify the enzymatic complex glucan synthase [33]. Evidence shows that increased chitin synthesis to compensate for the lack of glucan is strongly associated with caspofungin resistance [34]. In addition, the increase in chitin strengthens the cell wall [5]. Since its release, caspofungin has shown no activity against Cryptococcus, Fusarium, Trichosporon species, and filamentous fungi [35–37].

The inherent resistance of C. neoformans to caspofungin

Unraveling the innate resistance of C. neoformans is an intriguing challenge for researchers worldwide. Since caspofungin was released for use, its ineffectiveness against C. neoformans has been reported [7]. In general, changes in the hotspot regions of the FKS genes are commonly related to the resistance fungi to echinocandins [8]. Interestingly, the target 1,3-β-d-glucan synthase for caspofungin is found in C. neoformans [9]. Thompson et al. [9] showed that the gene encoding the catalytic subunit of glucan-synthase, FKS1, is essential in the species. Furthermore, the purified enzyme is sensitive to echinocandins in vitro [10]. This result suggests that resistance to caspofungin is independent of biochemical changes in the target [11]. So, how can we explain the high susceptibility of the target enzyme's activity to caspofungin and the high resistance of C. neoformans? (Figure 1).

Figure 1.

Figure 1.

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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.

Some studies hypothesize that changes in plasma membrane composition may explain the high tolerance of Cryptococcus. The absence of other important components in the plasma membrane makes the pathogen susceptible to the drug [10]. For example, the absence of the Cdc50 protein results in a defective plasma membrane, making caspofungin easier to penetrate and thus increasing the susceptibility of C. neoformans to echinocandin [11]. Cdc50 is a non-catalytic subunit of flippase that aids in phospholipid asymmetry in membranes in yeast cells [38].

In addition to the role of Cdc50, calcium channels are also important in the resistance of C. neoformans. Interestingly, the deletion of CRM1 (a protein located mainly in the endoplasmic reticulum [ER] membrane, responsible for the release of calcium from the ER into the cytosol) in a cdc50Δ mutant resulted in the return of resistance of C. neoformans to caspofungin [39]. Cao et al. [39] proposed that disruption of calcium homeostasis in mutant cells (cdc50Δ) led to caspofungin-induced cell death. On the other hand, loss of CRM1 at cdc50Δ promotes relief from increased intracellular calcium levels [40]. Recently, Tancer and coauthors [41] designed a synthetic peptide targeting the P4-ATPase based on the sequence of the Cdc50 loop region blocking its action. The peptide AW9-Ma efficiently blocked the flippase activity and thus the C. neoformans growth at a concentration of 64 μg/ml-1. Additionally, the peptide presented a synergistic effect with caspofungin. In the presence of peptide, the MIC of caspofungin toward wild-type C. neoformans was 4 μg/ml-1, the same for C. neoformans cdc50Δ mutant [41].

Another mechanism reported is the role of Puf4 in Cryptococcus resistance. Puf4 plays a crucial role in stabilizing genes involved in synthesizing important fungal cell wall components such as chitin, chitosan and α-glucan [42]. Kalem et al. [42] showed that the puf4 mutant of C. neoformans is susceptible to caspofungin, playing a key role in understanding the inherent resistance of cells to echinocandins.

The integrity of the C. neoformans membrane also influences resistance. Mutants of ERG4, involved in ergosterol synthesis; YSP2, which encodes a sterol transporter; CFT1, which encodes an iron transporter; and MYO1, involved in myosin synthesis, showed increased susceptibility to caspofungin [43]. This work shows that membranes with considerably altered compositions of strains with mutations are possibly more permeable to the drug.

Chitin synthesis seems to be increased during treatment with caspofungin. Pianalto et al. [12] demonstrated that the CHS1, CHS2, CHS4 and CHS7 genes involved in chitin synthesis have increased expression levels in response to caspofungin. This study also showed increased gene expression in synthesizing glucan and chitosan. These results corroborate that C. neoformans cells with reduced chitosan levels are more sensitive to cell wall stressors [44]. All of this seems to point to strengthening the cell wall and plasmatic membrane, protecting the cell from the drug's action.

Another interesting and important point is the development of efflux pumps. Intracellular levels of caspofungin are not high in C. neoformans cells [11]. The study conducted by Pianalto et al. [12] suggests that the lack of activity of caspofungin against Cryptococcus may also result from efflux pumps. However, this remains a little dark, as echinocandins are not typically substrates for efflux pumps [45,46].

Bioinformatic analysis of Caspofungin

Besides what was discussed in this manuscript, we also seek to find and suggest if caspofungin could have other targets inside the cell besides the classic enzymes targeted by echinocandin drugs. However, a toxicological assessment of Caspofungin's toxic effects was performed before analyzing the new target. The analysis used the canonical smile code extracted from the PubChem database (Caspofungin | C52H88N10O15 | CID 2826718 – PubChem [nih.gov]) [47]. Once the canonical smiles code of caspofungin was run analysis toxicological analysis of the Protox II server (ProTox-II – Prediction of TOXicity of chemicals [charite.de]) [48–50]. The predicted analysis is summarized in Table 1. The oral toxicity of caspofungin was predicted as LD50 at 3000 mg/kg, reaching classification number 5. The predicted toxicity classification runs from 1, the most toxic, to 6, no toxicity.

Table 1.

Toxicological parameters of Caspofungin assessed by bioinformatics analysis.

Classification Target Prediction Probability (%)
Organ toxicity Hepatotoxicity Active 69
Toxicity end points Carcinogenicity Inactive 61
Toxicity end points Immunotoxicity Inactive 99
Toxicity end points Mutagenicity Inactive 75
Toxicity end points Cytotoxicity Inactive 74
Tox21-Nuclear receptor signaling pathways Aryl hydrocarbon receptor (AhR) Inactive 96
Tox21-Nuclear receptor signaling pathways Androgen receptor (AR) Inactive 99
Tox21-Nuclear receptor signaling pathways Androgen receptor ligand binding domain (AR-LBD) Inactive 99
Tox21-Nuclear receptor signaling pathways Aromatase Inactive 95
Tox21-Nuclear receptor signaling pathways Estrogen receptor alpha (ER) Inactive 86
Tox21-Nuclear receptor signaling pathways Estrogen receptor ligand binding domain (ER-LBD) Inactive 94
Tox21-Nuclear receptor signaling pathways Peroxisome proliferator activated receptor gamma (PPAR-Gamma) Inactive 95
Tox21-Stress response pathways Nuclear factor (erythroid-derived 2)-like 2/antioxidant responsive element (nrf2/ARE) Inactive 98
Tox21-Stress response pathways Heat shock factor response element (HSE) Inactive 98
Tox21-Stress response pathways Mitochondrial membrane potential (MMP) Inactive 90
Tox21-Stress response pathways Phosphoprotein (tumor supressor) p53 Inactive 86
Tox21-Stress response pathways ATAD5 Inactive 98
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The toxicity analysis predicted an organ toxicity of caspofungin focused on hepatotoxicity (Table 1) with a probability of 69%. This result presented by bioinformatics analysis agrees with some studies already published. Indeed, caspofungin has presented toxicity to the liver. It is well tolerated by patients, including children and transplanted patients [51–54]. Regarding other toxic parameters, caspofungin presented safe predictions.

After the toxicological analysis of caspofungin, the canonical smiles code was employed for target fishing on the target net server (www.targetnet.scbdd.com/). The target fishing analysis came out with HDCA4 as the potential new target of caspofungin. Based on that, a bioinformatic study was performed on HDCA4 from C. neoformans and Homo sapiens. The global alignment of HDCA4 from C. neoformans and H. sapiens revealed low similarity between both sequences (Supplementary Figure S1), confirmed by 3D structure analysis (Figure 2).

Figure 2.

Figure 2.

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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).

Molecular docking analysis revealed the interaction between caspofungin with HDCA4 from H. sapiens (Figure 3A). A higher number of polar interactions was revealed by a 2D map made with the Discover software (Figure 3B). The 2D map made with Ligplot software revealed some hydrophobic interaction (Figure 3C). Regarding the polar interaction caspofungin made interactions such as a salt bridge, conventional H-H bond, C-H bond and Alkyl, respectively, with Asp317, Arg233, Gly283 and Lys279 (Figure 3B).

Figure 3.

Figure 3.

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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.

Regarding the interaction with HDCA4 from C. neoformans, caspofungin interacted in a completely different region (Figure 4A). Many polar interactions were conventional hydrogen bonds with Ala230, Arg229, Leu107 and Arg203 (Figure 4B). For C. neoformans, HDCA4 presented a smaller number of hydrophobic interactions (Figure 4C) than H. sapiens does. It is important to notice that caspofungin interacts at different spots with HDCA4 from H. sapiens and C. neoformans (Figures 3A & 4A). In the case of C. neoformans, caspofungin interacts within a region closer than the active site of HDCA4, which led us to suggest an impairment in its activity.

Figure 4.

Figure 4.

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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.

Our bioinformatic data suggests a new target of caspofungin that could be explored further for experimental analysis. This is not the first time a new target has been proposed to interact with caspofungin. Siala et al. [55] reported that caspofungin increases the action of fluoroquinolones against Staphylococcus aureus by interacting and inhibiting the activity of N-acetylglucosamine transferase.

Another study by Reis et al. [56] revealed that a combination of caspofungin and brilacidin enhances caspofungin effects on resistant a strain of Aspergillus fumigatus. Brilacidin is a mimetic human defense peptide that affects the integrity of the cell wall of A. fumigatus, enhancing the movement of caspofungin and increasing its concentration within the cell [56]. The authors also reported that brilacidin enhanced the activity of caspofungin against C. neoformans [56]. The authors revealed that alone caspofungin could not inhibit C. neoformans growth even at a concentration of 32 μg/ml-1. In contrast, in the presence of brilacidin, the concentration of caspofungin to reach fungicidal activity dropped to 0.25 μg/ml-1 [56].

Our data, and that presented by Siala et al. [55] and Reis et al. [56] indicated that caspofungin could have an alternative intracellular target different than the canonical one, which could happen even in C. neoformans. This discussion suggests the redirection of caspofungin to new targets to make pathogens susceptible again to caspofungin action.

Conclusion

It is possible to suggest that the intrinsic resistance of C. neoformans to caspofungin could be reverted by trying to find a new target to which caspofungin can be improved and thus bring back the caspofungin to the hall of drugs that can be useful again in the treatment of infection caused by C. neoformans.

Future perspective

Our review brought to light new information that could open new ways to employ caspofungin in treating fungal infections, mainly C. neoformans. As discussed, many Fungi have intrinsic resistance to the canonical mechanism of action of caspofungin. Nevertheless, as discussed above, caspofungin could have new targets and open new ways for the application of caspofungin.

One of the possibilities that should be investigated in the future is the association of caspofungin with other molecules. For example, the association of caspofungin with the peptide brilacidin improved caspofungin's action against A. fumigatus and C. neoformans [56]. The association of caspofungin with other molecules is possibly a great way to bring its effectiveness against resistance pathogens.

Another important point that is worth analyzing is seeking new targets for caspofungin. As revealed by bioinformatic analysis, caspofungin interacts with a histone deacetylase. Although the results predicted by bioinformatics require confirmation, they open a new perspective that demands further analysis to be confirmed. Therefore, opens up a new field of study for caspofungin to be fulfilled in upcoming years.

Supplementary Material

Supplementary Figure S1
IFMB_A_2340265_SM0001.pdf (291.4KB, pdf)

Funding Statement

PFN Souza is thankful for the senior researcher grant from CNPq at process number 305003/2022-4.

Author contributions

TKB Aguiar, ACM Costa, NAS Neto, DMS Brito, CDT Freitas, JMM Neto, FP Mesquita and PFN Souza performed the conception, and the study design was written and approved the final version for submission.

Financial disclosure

PFN Souza is thankful for the senior researcher grant from CNPq at process number 305003/2022-4. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

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.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

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