Anti-amoebic potential of azole scaffolds and nanoparticles against pathogenic Acanthamoeba

Abstract

Acanthamoeba spp. are free living amoeba (FLA) which are widely distributed in nature. They are opportunistic parasites and can cause severe infections to the eye, skin and central nervous system. The advances in drug discovery and modifications in the chemotherapeutic agents have shown little improvement in morbidity and mortality rates associated with Acanthamoeba infections. The mechanism-based process of drug discovery depends on the molecular drug targets present in the signaling pathways in the genome. Synthetic libraries provide a platform for broad spectrum of activities due to their desired structural modifications. Azoles, originally a class of synthetic anti-fungal drugs, disrupt the fungal cell membrane by inhibiting the biosynthesis of ergosterol through the inhibition of cytochrome P450 dependent 14α-lanosterol, a key step of the sterol pathway. Acanthamoeba and fungi share the presence of similar sterol intermediate, as ergosterol is also the major endproduct in the sterol biosynthesis in Acanthamoeba. Sterols present in the eukaryotic cell membrane are one of the most essential lipids and exhibit important structural and signaling functions. Therefore, in this review we highlight the importance of specific targeting of ergosterol present in Acanthamoebic membrane by azole compounds for amoebicidal activity. Previously, azoles have also been repurposed to report antimicrobial, antiparasitic and antibacterial properties. Moreover, by loading the azoles into nanoparticles through advanced techniques in nanotechnology, such as physical encapsulation, adsorption, or chemical conjugation, the pharmacokinetics and therapeutic index of the drugs can be significantly improved. The current review proposes an important strategy to target Acanthamoeba using synthetic libraries of azoles and their conjugated nanoparticles for the first time.

Antiamoebic Properties of Ceftriaxone and Zinc-Oxide–Cyclodextrin-Conjugated Ceftriaxone

“…Inorganic nanoparticles including metal nanoparticles have been incorporated in various medical applications due to their affordable production, versatility, low toxicity, and robustness [ 39 ]. When it comes to amoebae, several nanoparticles bearing antibiotics, namely silver- and gold-based nanocarriers have proved efficacious against amoebae [ 31 , 39 , 40 , 41 ] Other studies employed tannic acid-modified silver, azole, dysprosium-based, and cobalt phosphate nanoparticles and reported marked anti- Acanthamoebic activity [ 42 , 43 , 44 , 45 ]. Due to its potency against bacteria, the nanocarrier ZnO has been implemented in various biomedical applications including water treatment [ 46 ].…”

Applications of medicinal chemistry for drug discovery against Acanthamoeba infections

“…4 However, Acanthamoeba is also increasingly recognized as an important cause of keratitis in noncontact lens wearers. [28][29][30] GAE is a progressive infection of the CNS, that occurs mostly among the immunocompromised individuals, such as those infected with human immunodeficiency virus or acquired immunodeficiency syndrome, organ transplant recipients, patients with diabetes, systemic lupus erythematosus, cancer patients undergoing chemotherapy, as well as a few cases in immunocompetent individuals. [31][32][33] Brain-eating amoebae including Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp.…”

“…The risk factor of AK is associated with contact lens usage and poor lens hygiene 4 . However, Acanthamoeba is also increasingly recognized as an important cause of keratitis in noncontact lens wearers 28–30 …”

Nanovehicles in the improved treatment of infections due to brain-eating amoebae

“…Hence, innovative strategies utilizing nanoparticles (NPs), graphene, and peptide modified carriers are proposed as advanced methods that may increase drug delivery across the BBB (Barani et al 2021;Wang et al 2021), resulting in improved treatment of amoebic brain infections. Encouragingly, recent studies have depicted nanotechnology in the improvement of drug efficacy against amoebae (Anwar et al 2019a, b, c, d;Mungroo et al 2020;Rajendran et al 2019;Walvekar et al 2020). Moreover, nanovehicles have high loading capacity, enhanced permeability, and the possibility to encompass several agents within one carrier, which have retention effects that are useful in active and passive targeting of parasites (Zeinali et al 2020).…”