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bioRxiv2025

Drug screen reveals new potent host-targeted antivirals against Mpox virus

Mpox virus (MPXV), a re-emerging zoonotic threat, has caused outbreaks in non-endemic regions through respiratory, sexual, and close-contact transmission. The increased transmissibility of Clade IIb fueled the 2022 global outbreak, with 2024 Clade Ib spread in the Democratic Republic of Congo further escalating concern. Both outbreaks were declared public health emergencies by the WHO. Although tecovirimat (TPOXX) has been used off-label for Mpox, its limited effectiveness highlights the critical need for newer antivirals for MPXV. We conducted high- throughput antiviral drug screening using a host-directed kinase inhibitor library composed of 2,750 compounds against 2022 Clade IIb MPXV. Our primary screen identified 138 compounds preventing MPXV cytopathic effects, including multiple inhibitors of EGFR, PI3K-mTOR, and Ras/Raf, as well as apoptosis and autophagy regulators. Secondary and tertiary screenings yielded a shortlist of potent, nontoxic antiviral compounds that inhibited MPXV replication. Three selected compounds, IRAK4-IN-6, SM-7368, and KRAS inhibitor-10, reduced MPXV-induced cell death in primary human epidermal keratinocytes. IRAK4-IN-6 and SM-7368 were also found to modulate NF-{kappa}B and STING signaling. Furthermore, these compounds were found effective in reducing skin lesions and viral burden in a mouse model of MPXV skin infection. Together, our study reveals new classes of antiviral compounds against MPXV, offering promising candidates for future clinical development.

microbiology↗

bioRxiv2022

Niclosamide loaded Eudragit EPO nanoparticles show enhanced Candida biofilm penetration, trigger biofilm detachment and protect from mucosal candidiasis

Candida albicans biofilms are a complex multilayer community of cells that are resistant to almost all classes of antifungal drugs. The bottommost layers of biofilms experience nutrient limitation where C. albicans cells are required to respire. We previously reported that a protein Ndu1 is essential for Candida mitochondrial respiration; loss of NDU1 causes inability of C. albicans to grow on alternative carbon sources and triggers early biofilm detachment. Here, we screened a repurposed library of FDA approved small molecule inhibitors, to identify those that prevent NDU1-associated functions. We identified an anti-helminthic drug, Niclosamide (NCL), which not only prevented growth on acetate, C. albicans hyphenation and early biofilm growth, but also completely disengaged fully grown biofilms of drug resistant C. albicans and C. auris from their growth surface. To overcome the sub-optimal solubility and permeability of NCL that is well-known to affect its in vivo efficacy, we developed NCL encapsulated Eudragit EPO (an FDA-approved polymer) nanoparticles (NCL-EPO-NPs) with high niclosamide loading, that also provided long-term stability. The developed NCL-EPO-NPs completely penetrated mature biofilms and attained anti-biofilm activity at low microgram concentrations. NCL-EPO-NPs induced ROS activity in C. albicans, and drastically reduced oxygen consumption rate in the fungus, similar to that seen in an NDU1 mutant. NCL-EPO-NPs also significantly abrogated mucocutaneous candidiasis by fluconazole resistant strains of C. albicans, in mice models of oropharyngeal and vulvovaginal candidiasis. To our knowledge, this is the first study that targets biofilm detachment as a target to get rid of drug-resistant Candida biofilms, and uses nanoparticles of an FDA approved non-toxic drug to improve biofilm penetrability and microbial killing.

microbiology↗