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15 Aspergillus Therapeutics: Future Agents
373
15.2.6 MGCD290
MGCD290 is a fungal histone deacetylase inhibitor currently in phase II clinical
trials that exhibits synergistic effect with other antifungals, such as echinocandins
and azoles. It is mainly aimed at being used as a combination/add on treatment
option in case of azole and echinocandins-resistant strains of Aspergillus, Mucor,
and Candida spp.
15.2.7 Tetrazoles (VT-1129/VT-1161/VT-1598)
Azole class of antifungals includes the imidazoles (ketoconazole, clotrimazole, and
miconazole) (Liu etal. 2014) and triazoles (uconazole and itraconazole) (LassFlörl 2011). Second generation or newer generation of triazoles (voriconazole,
posaconazole, isavuconazole, and ravuconazole) has been developed recently with
extended spectrum of activity and lesser toxicities (Jović etal. 2019). The next generation of azoles, also known as tetrazoles, is currently under development and
includes three drugs, VT-1129, VT-1161, or oteseconazole and VT-1598 (Rauseo
etal. 2020). Tetrazoles overcome the most glaring shortcomings of the currently
available azoles as tetrazoles have selective action against the fungal cytochrome
P450 enzyme; specically, it has higher afnity for lanosterol 14α demethylase, i.e.,
CYP51 (Warrilow etal. 2016).
These drugs are active against Candida spp. and mucormycosis, but VT-1598 has
a broader spectrum of activity and shows antifungal activity against Aspergillus spp.
and endemic mycoses. In a study conducted on neutropenic mice, this drug also
showed potential activity against Candia auris (Wiederhold etal. 2019).
VT-1161 is presently the closest to licensing, and has recently completed phase
III trials for vulvovaginal candidiasis (clinicaltrials ID: NCT03840616 2019d;
NCT03562156 2018c). VT-1598 is in phase I trial (clinicaltrials ID: NCT04208321
2020c), whereas VT-1129 is in pre-clinical stage.
15.2.8 Nikkomycin Z
Chitin, a component of the fungal cell wall, is synthesized by chitin synthase
enzymes. Nikkomycin Z inhibits these enzymes and thus exerts antifungal effects
after oral administration (Stenland etal. 2013). This is a promising novel drug that
shows minimal toxicity owing to the lack of these enzymes in the human cells. The
drug was discovered more than 50years ago, but its potential use as an antifungal
agent was realized in the recent times and clinical trials were conducted in Arizona,
USA.The initial, phase I trial (clinicaltrials ID: NCT00834184 2008) demonstrated
excellent safety prole of the drug and two phase II studies were initiated but were
later terminated due to issues related to study participants’ recruitment-related challenges (clinicaltrials ID: NCT01647256 2012) or inability of the researchers to raise
funding (clinicaltrials ID: NCT00614666 2007).
374
The drug is being developed mainly for its activity against the agents of endemic
mycoses, namely, Coccidioides spp., Blastomyces spp. and Histoplasma spp.
Although Nikkomycin lacks activity against molds and most Candida spp., it has
synergistic potential when combined with other antifungals, such as echinocandins
and azoles for extending the spectrum against Aspergillus spp. and Candida spp. (Li
and Rinaldi 1999).
Y. Bansal et al.
15.2.9 VL-2397
VL-2397 is a drug bearing structurally similarities with ferrichrome, a siderophore
molecule that acts as an aluminum chelator. It possesses antifungal properties and
has been shown to be active against a variety of fungi, such as Aspergillus (including azole-resistant Aspergillus fumigatus), Candida glabrata, Cryptococcus, and
Trichosporon spp. A phase I study found favorable safety prole of the drug
(Mammen etal. 2019) and a phase II trial (Clinical trials ID: NCT03327727 2018d)
was started but later terminated owing to business decision as per trials registry
website) were conducted, but the drug is not under active development as of now.
15.2.10 T-2307/ATI-2307
The exact mechanism of action of this drug is under study and it appears to disrupt
the mitochondrial activity in the fungal cells thereby exerting antifungal properties
(Gerlach et al. 2021). Chemically, it is an arylamidine compound that is active
against Candida spp., Aspergillus spp., and Fusarium spp. The drug is in initial
phase of development.
15.2.11 Encochleated Amphotericin-B
Amphotericin B is a polyene antifungal that acts by binding to sterols and increasing cell permeability and leakage. The signicant toxicities observed with the conventional formulations were reduced after the introduction of liposomal preparations
(especially renal toxicity) and the development of encochleated amphotericin B
further aims to drastically reduce the toxicity to as low as possible. The mechanism
of action of the drug remains the same, but the targeted delivery of amphotericin B
to macrophages and reticuloendothelial system is achieved by encapsulating the
drug in a lipid bilayer of cochleate structure containing high calcium ion concentration. Such a formulation avoids release of amphotericin B in the stomach but unfolds
to release the drug inside the macrophages when it detects a low calcium ion concentration outside the cochleate structure.
Adequate drug concentration levels have been demonstrated in liver, spleen, and
kidneys after oral administration. The modied drug has shown activity against
invasive fungal infections candidiasis, aspergillosis, and Cryptococcus meningitis
15 Aspergillus Therapeutics: Future Agents
375
(Delmas etal. 2002). The drug is presently in phase II clinical trials for oral administration in a dose of 200–800mg.
15.2.12 SUBA-Itraconazole
Itraconazole is a rst-generation triazole antifungal with broad spectrum of activity
against a variety of fungi, but its limited bioavailability of around 50–55% is a hindrance in its clinical utility to some extent. To increase its effectiveness after oral
administration and to reduce the variability in bioavailability from patient to patient,
a super bioavailable itraconazole has been developed (Abuhelwa etal. 2015). The
drug is designed to be delivered in a pH dependent polymer matrix composed of
Hypromellose phthalate that increases the bioavailability signicantly (Sardana and
Mathachan 2021). The drug was approved for use in systemic fungal infections by
the FDA in 2018.
15.2.13 Immunotherapy
The current treatment options in aspergillosis have substantial gaps which need to
be bridged. Immunotherapy is an upcoming option in this context. Although it
appears promising, it is still in its infancy with most of the developments being
restricted to pre-clinical models and clinical trials. Fungal organisms are unique in
comparison with other pathogens, as they have a cell wall composed of chitin, glucans and glycoproteins which is a protective shell acting as a structural barrier and
as a savior against osmotic lysis (Boyer etal. 2023). Aspergillus species produce,
mycotoxin ‘Aatoxin,’ causing damage to the host. These fungi have mechanisms
to evade host immune defense thus causing disease. Nevertheless, immunotherapy
offers hope to interrupt these interactions and seems to be the ‘New Horizon’ bringing joy by improving overall survival in patients with invasive fungal infections.
The schema of immunotherapy revolves around vaccines, targeted activation of
phagocytes, T cells, check point inhibitors, antibodies and cytokines/ chemokines,
antimicrobial peptides, and gene therapy (Boyer etal. 2023; Nami et al. 2019a).
These are briey discussed as under:
1. Antibodies: The fungal heat shock protein-HSP90 is a chaperone implicated in
antifungal resistance. Benecial effects of analogs of geldanamycin which
inhibits HSP90 have been seen in combating Aspergillus infections in combina-
tion with antifungal drugs.
2. Cytokine Therapy—Recombinant Human Interferon γ (IFN-γ): This is currently
the standard of care in prophylaxis of invasive aspergillosis in patients with
chronic granulomatous disease and chronic pulmonary aspergillosis.
3. Immune Check Point Inhibitor Therapy: In mouse sepsis model, administration
of Amphotericin B in combination with anti-programmed death-1 (anti-PD-1)
resulted in reduction of post-sepsis aspergillosis (Vu etal. 2020). Presumably,
376
Y. Bansal et al.
the blockade of PD-1 stimulates exhausted T cells and antigen presenting cells
by CD86 upregulation and increased IFN-γ generation with dampening of interleukin- 10 (IL-10) levels. This serves as a futuristic strategy in overcoming deleterious effects of fungal infection.
4. T cells: Allogeneic stem cell transplant recipients with invasive aspergillosis
have shown to gain from adoptive T-cell transfer, wherein patients are reinfused
with their CD4 + T cells which are invigorated ex vivo with Aspergillus.
Employment of chimeric antigen receptor (CAR) CD8+ T cells, which exhibit
articial T-cell receptor specic to Aspergillus, appears fruitful. This approach
has been extended further recently (Kumaresan etal. 2018) where the researchers developed a CAR targeting β-glucan, present in fungal cell wall using the
extracellular domain of Dectin-1 which binds to β-glucan. Mice treated with
these showed reduced hyphal growth of Aspergillus. It is drawn that the use of
bioengineered CAR-T cell therapy has a capability to benet patients inicted
with invasive fungal infections.
5. Gene Therapy: Aspergillosis is a signicant cause of mortality in patients with
chronic granulomatous disorder (CGD), a primary immunodeciency state.
Recently, gene therapy using a gamma-retroviral vector harboring a variant of
defective glycoprotein-gp91
phox
was utilized to treat pulmonary Aspergillus
nidulans infection in a patient with CGD (Nami etal. 2019a).
6. Vaccines: Development of vaccines against fungal infections is a challenge.
These are limited to mice models as of now and await clinical human trials
(Nami etal. 2019b). As regards Aspergillus, the antigens or strains are Aspergillus
fumigatus crude culture ltrate antigens, Asp 3f, Asp 16f, viable conidia, hyphal
sonicate, and epitope p41 from the cell wall glucanase (Crf1). These are subunit
or recombinant vaccines with underlying antibody and cellular immune response
mechanisms involving CD4+ T helper cells—Th1 cells producing IFN-γ and
IL-2 or production of antibodies.
15.2.14 Drug Repurposing
Utilization of drugs which are already authorized for therapeutics in diseases other
than those caused by fungi to treat fungal infections is drug repurposing or drug
repositioning (Pushpakom etal. 2019). This novel concept leads to an enormous
reduction in time, labor, and nance involved in developing new antifungal agents.
Auranon, which is a FDA-approved disease-modifying gold preparation for treatment of rheumatoid arthritis, has shown antifungal activity against A. fumigatus
(Thangamani etal. 2017). Yet, another drug with promising invivo antifungal action
against A. fumigatus infection is sertraline, a selective serotonin reuptake inhibitor
with proven anti-depressant properties (Treviño-Rangel et al. 2019). Recently,
tamoxifen, a selective estrogen receptor modulator in use for treating breast cancer,
has shown good activity against A. fumigatus, A. avus, A. terreus, and A. niger in
the range of 16–64μg/mL (Pasrija and Kundu 2018).
15 Aspergillus Therapeutics: Future Agents
377
15.3 Conclusions: TheWay Forward
Emergence of drug resistance among Aspergillus spp. is a matter of concern as they are one
of the commonest opportunistic infections seen in humans. A lot of drugs are in pipeline,
comprising of both novel classes as well as drugs belonging to existing classes of antifungals.
Though not all are guaranteed to be licensed, but they bring hope to the future of antifungal
therapy. In addition to the availability of new antifungals capable of action against drugresistant fungi, it is important to maintain the continued effectiveness of these antifungals
using them judiciously and practicing antifungal stewardship (Singla and Bansal 2024).
Diagnostic microbiology/mycology laboratories, in collaboration with an interdisciplinary
team of clinicians, need to strive for diagnostic stewardship (World Health Organization
2016; Hueth et al. 2022) and support antifungal therapy by generating quality AFST
data.Conict of InterestThe authors declare that they have no conicts of interest.
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Recent Advances intheManagement
ofAspergillosis
16
ChhaviGupta andSajadAhmadDar
Abstract
Aspergillus spp. is a ubiquitous lamentous mold, encompassing a wide spec-
trum ranging from saprophytic colonization and allergic syndrome, localized or
disseminated depending upon the interplay between host immune response and
virulence of pathogen, and degree of immunosuppression and hyperactivity. The
risk factors for invasive aspergillosis include inherited or acquired neutrophil
defects, hematological malignancies, solid-organ malignancies with profound
neutropenia, hematopoietic stem cell transplant, solid-organ transplants, pro-
longed or high-dose corticosteroids or immunosuppressants, advance acquired
immunodeciency syndromes, reactive airway disease, chronic lung disease,
diabetes mellitus (DM), acute or chronic liver disease, and rheumatological con-
ditions; Inuenza and COVID-19 are new risk factors associated with high mor-
tality. With the increasing complexities of infections, host immune status, drug,
and emerging antifungal resistance, the management of Aspergillus spp. infec-
tions is becoming a challenge. Therapeutic drug monitoring, combination ther-
apy, and alternative antifungal agents as salvage therapy are the emerging
strategies. Consequently, novel antifungal agents with newer targets and struc-
tural modications of existing agents are in the pipeline. In this chapter, we will
discuss the recent concepts and newer agents in the management of Aspergillus
spp. infections.
C. Gupta (*)
Department of Infectious Disease, Yashoda Superspeciality Hospital, Delhi NCR, India
Infectious Disease, AIIMS, New Delhi, India
S. A. Dar
Research and Scientic Studies Unit, College of Nursing, Jazan University,
Jazan, Saudi Arabia
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
S. Hameed, P. Vijayaraghavan (eds.), Recent Advances in Human Fungal
Diseases, https://doi.org/10.1007/978-981-97-4909-6_16
383