Fralin Life Sciences Institute

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https://hdl.handle.net/10919/25796
Note: In 2019, the Biocomplexity Institute became part of the Fralin Life Sciences Institute.

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Browsing Fralin Life Sciences Institute by Author "Abutaleb, Nader S."

Now showing 1 - 4 of 4
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    Auranofin exerts antibacterial activity against Neisseria gonorrhoeae in a female mouse model of genital tract infection
    Elhassanny, Ahmed E. M.; Abutaleb, Nader S.; Seleem, Mohamed N. (PLOS, 2022-04-21)
    Neisseria gonorrhoeae has been classified by the U.S. Centers for Disease Control and Prevention as an urgent threat due to the rapid development of antibiotic resistance to currently available antibiotics. Therefore, there is an urgent need to find new antibiotics to treat gonococcal infections. In our previous study, the gold-containing drug auranofin demonstrated potent in vitro activity against clinical isolates of N. gonorrhoeae, including multidrug-resistant strains. Therefore, the aim of this study was to investigate the in vivo activity of auranofin against N. gonorrhoeae using a murine model of vaginal infection. A significant reduction in N. gonorrhoeae recovered from the vagina was observed for infected mice treated with auranofin compared to the vehicle over the course of treatment. Relative to the vehicle, after three and five days of treatment with auranofin, a 1.04 (91%) and 1.40 (96%) average log(10)-reduction of recovered N. gonorrhoeae was observed. In conclusion, auranofin has the potential to be further investigated as a novel, safe anti-gonococcal agent to help meet the urgent need for new antimicrobial agents for N. gonorrhoeae infection.
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    Dithiocarbamates effectively inhibit the alpha-carbonic anhydrase from Neisseria gonorrhoeae
    Giovannuzzi, Simone; Abutaleb, Nader S.; Hewitt, Chad S.; Carta, Fabrizio; Nocentini, Alessio; Seleem, Mohamed N.; Flaherty, Daniel P.; Supuran, Claudiu T. (Taylor & Francis, 2022-01-01)
    Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the alpha-class carbonic anhydrase (CA, EC 4.2.1.1) from Neisseria gonorrhoeae, NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. K(I)s ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against N. gonorrhoeae, and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 mu g/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.
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    Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections
    Hagras, Mohamed; Abutaleb, Nader S.; Sayed, Ahmed M.; Salama, Ehab A.; Seleem, Mohamed N.; Mayhoub, Abdelrahman S. (PLOS, 2021-11-04)
    To minimize the intrinsic toxicity of the antibacterial agent hydrazinyloxadiazole 1, the hydrazine moiety was replaced with ethylenediamine (compound 7). This replacement generated a potent antifungal agent with no antibacterial activity. Notably, use of a 1,2-diaminocyclohexane moiety, as a conformationally-restricted isostere for ethylenediamine, potentiated the antifungal activity in both the cis and trans forms of N-(5-(2-([1,1'-biphenyl]-4-yl)-4-methylthiazol-5-yl)-1,3,4-oxadiazol-2-yl)cyclohexane-1,2-diamine (compounds 16 and 17). Both compounds 16 and 17 were void of any antibacterial activity; nonetheless, they showed equipotent antifungal activity in vitro to that of the most potent approved antifungal agent, amphotericin B. The promising antifungal effects of compounds 16 and 17 were maintained when assessed against an additional panel of 26 yeast and mold clinical isolates, including the Candida auris and C. krusei. Furthermore, compound 17 showed superior activity to amphotericin B in vitro against Candida glabrata and Cryptococcus gattii. Additionally, neither compound inhibited the normal human microbiota, and both possessed excellent safety profiles and were 16 times more tolerable than amphotericin B.
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    Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases
    An, Weiwei; Holly, Katrina J.; Nocentini, Alessio; Imhoff, Ryan D.; Hewitt, Chad. S.; Abutaleb, Nader S.; Cao, Xufeng; Seleem, Mohamed N.; Supuran, Claudiu T.; Flaherty, Daniel P. (Taylor & Francis, 2022-12-31)
    Vancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (K (i)) against the E. faecium alpha-CA (Ef alpha-CA) and gamma-CA (Ef gamma-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and K (i) for each CA.