Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections.

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for the treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at concentrations of 0.5 µg/ml and 2 µg/ml, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3 log10 within 6 h. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficilein vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit the growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium, and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.

Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system.

Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC50) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC50 1.13-2.01 µM). Bexarotene demonstrated the highest Cmax:EC50 ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.

Experimental Evidence for Diiodohydroxyquinoline-Induced Neurotoxicity: Characterization of Age and Gender as Predisposing Factors.

Though quinoline anti-infective agents-associated neurotoxicity has been reported in the early 1970s, it only recently received regulatory recognition. In 2019, the European Medicines Agency enforced strict use for quinoline antibiotics. Thus, the current study evaluates the relation between subacute exposure to diiodohydroxyquinoline (DHQ), a commonly misused amebicide, with the development of motor and sensory abnormalities, highlighting age and gender as possible predisposing factors. Eighty rats were randomly assigned to eight groups according to their gender, age, and drug exposure; namely, four control groups received saline (adult male, adult female, young male, and young female), and the other four groups received DHQ. Young and adult rats received DHQ in doses of 176.7 and 247.4 mg/kg/day, respectively. After 4 weeks, rats were tested for sensory abnormality using analgesiometer, hot plate, and hind paw cold allodynia tests, and for motor function using open field and rotarod tests. Herein, the complex behavioral data were analyzed by principal component analysis to reduce the high number of variables to a lower number of representative factors that extracted components related to sensory, motor, and anxiety-like behavior. Behavioral outcomes were reflected in a histopathological examination of the cerebral cortex, striatum, spinal cord, and sciatic nerve, which revealed degenerative changes as well demyelination. Noteworthy, young female rats were more susceptible to DHQ's toxicity than their counterparts. Taken together, these findings confirm previous safety concerns regarding quinoline-associated neurotoxicity and provide an impetus to review risk/benefit balance for their use.