<p>In the past few decades, invasive mycosis has become a
growing threat to global health, afflicting millions of people and claiming the
lives of more than 1.5 million patients every year. Moreover, the economic
burden of mycotic infections has become
increasingly exhausting especially with the recent increases in the number of
the high-risk population, the immunocompromised individuals. In the USA, the cost
incurred by mycotic infections was estimated to be of more than $7.2 billion only in 2017. Of
particular concern, <i>Candida</i> species are the most common fungal pathogens
that infect humans, resulting in considerable morbidities and mortality rates
that often exceed 50%. Unfortunately, the antifungal drug discovery is
currently unable to keep pace with the urgent demand for more effective therapeutic
options. Further complicating the situation is the recent emergence of
multidrug-resistant species such as <i>Candida</i> <i>auris</i>, triggering
outbreaks of deadly Candidemia across the globe. Given the risks inherent to
the traditional de-novo drug discovery, combinatorial therapeutics stands out
as a promising tool to hamper drug resistance and extend the clinical utility
of the existing drugs. In this study, we assembled and screened ~3147 FDA-approved
drugs and clinical molecules against fluconazole-resistant <i>C. albicans</i>
and <i>C. auris</i> isolates, for the aim of restoring the antifungal activity
of azole antifungals against drug-resistant <i>Candida </i>species. The screen
revealed five promising hits: pitavastatin (antihyperlipidemic), ospemifene
(estrogen receptor modulator), sulfa antibacterial drugs, lopinavir
(antiviral), and aprepitant (antiemetic).</p>
<p>All identified hits demonstrated variable
azole chemosensitizing activities depending on the tested <i>Candida</i>
species and the azole drug. Pitavastatin displayed broad-spectrum synergistic
interactions with both fluconazole and voriconazole against isolates of <i>C.
albicans</i>, <i>C. glabrata</i>, and <i>C. auris</i>. Ospemifene was able to
interact synergistically with itraconazole against multiple fungal isolates
including <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i> species.
Sulfa drugs displayed potent synergistic activities with different azoles
against <i>C. albicans</i>, however, a limited efficacy was observed against
efflux-hyperactive isolates such as <i>C. auris</i>. On the other hand, both
lopinavir and aprepitant exerted potent and broad-spectrum synergistic
activities with itraconazole and were effective against multiple <i>Candida</i>
species including <i>C. albicans</i>, <i>C. auris</i>, <i>C. glabrata</i>, <i>C.
krusie</i>, <i>C. tropicalis</i>, and <i>C. parapsilosis</i>. Furthermore, using
<i>Caenorhabditis elegans</i> as an infection model, all drug combinations
significantly reduced the fungal burden in the infected nematodes and
significantly prolonged their survival as compared to single-drug treatments. Multiple
phenotypic and molecular assays indicted that the identified hit compounds use
distinct mechanisms to enhance the antifungal activity of azole drugs. These
mechanisms include efflux pump inhibition, interference with the folate
biosynthesis and disturbance of iron homeostasis. Taken together, this study
reveals novel and potent azole chemosensitizing agents effective against multiple
azole-resistant isolates and opens the door for more investigations to assess
their clinical potential in human medicine as promising antifungal adjuvants.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12210242 |
| Date | 21 June 2022 |
| Creators | Hassan Elsayed Eldesouky (8715252) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/REPURPOSING_FDA-APPROVED_DRUGS_FOR_OVERCOMING_AZOLE_RESISTANCE_IN_CANDIDA_SPECIES/12210242 |
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