Repurposing the Antiamoebic Drug Diiodohydroxyquinoline for Treatment of Clostridioides difficile Infections

Abstract

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. difficile in 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.

In vitro and in vivo activities of the carbonic anhydrase inhibitor, dorzolamide, against vancomycin-resistant enterococci

“…A time-kill assay was performed for dorzolamide and linezolid against E. faecium HM-952, following a method described previously ( Abutaleb & Seleem, 2020a ; Abutaleb & Seleem, 2020c ).…”

“…In addition, VRE infections are associated with increased rates of mortality as well as high economic burden due to extended periods of hospitalizations ( Stagliano et al, 2017 ). The U.S. Centers for Disease Control and Prevention (CDC) recently reported that VRE infections contributed to nearly 55,000 hospitalizations in the United States in 2017, which resulted in a 10% mortality rate and cost nearly $540 million in healthcare costs ( Abutaleb & Seleem, 2020c ).…”

“…Drug repurposing is an efficient approach to drug discovery that saves both time and costs associated with drug innovation ( AbdelKhalek et al, 2018 ; AbdelKhalek et al, 2019 ; Abutaleb & Seleem, 2020a ; Abutaleb & Seleem, 2020b ; Abutaleb & Seleem, 2020c ; Brown, 2015 ; Mohammad et al, 2018 ; Younis et al, 2017 ). In an effort to meet the critical need for development of new, effective anti-VRE agents, we identified the FDA-approved carbonic anhydrase inhibitors (CAIs) acetazolamide, methazolamide and ethoxzolamide as promising anti-VRE agents ( Younis et al, 2017 ).…”

N-(1,3,4-Oxadiazol-2-yl)Benzamides as Antibacterial Agents against Neisseria gonorrhoeae

“…The minimum bactericidal concentration (MBC) of these drugs was tested by plating 4 µL from wells with no growth onto chocolate agar II plates. Plates were then incubated at 37 ° C in the presence of 5% CO 2 for 24 h. The MBC was categorized as the lowest concentration that reduced bacterial growth by 99.9% [ 45 , 46 , 47 ].…”

“…Plates were incubated at 37 ° C for at least 18 h before recording the MBC. The MBC was categorized as the lowest concentration that reduced bacterial growth by 99.9% [ 45 , 46 , 47 ].…”