Evaluation of bisphenylthiazoles as a promising class for combating multidrug-resistant fungal infections

Abstract

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.

Novel combinatorial approach: Harnessing HIV protease inhibitors to enhance amphotericin B’s antifungal efficacy in cryptococcosis

“…Therefore, we investigated whether co-administration of different PIs would impact the cytotoxicity of AmB using the Vero cell line. Consistent with previous studies, AmB at its most frequent MIC against Cryptococcus isolates (1 μg/mL) did not exhibit any toxicity on treated Vero cells [ 56 , 57 ]. Similarly, adding PIs at the tested concentration did not affect the safety profile of AmB, indicating the safety of this combination on renal tissue.…”

Exploring novel microbial metabolites and drugs for inhibiting Clostridioides difficile

“…Six metabolites were excluded because they were previously reported, including tinidazole, tioconazole, miconazole, and choloroxine ( 48 ); lithocholic acid ( 57 ); and octenidine dihydrochloride ( 58 ). The other 12 unique compounds, which were not reported against C. difficile previously, were selected for further investigation ( Table 2 ).…”

“…The eight active metabolites and drugs were assessed for their antibacterial activity against reference strains of the human normal gut flora, following established procedures ( 43 , 46 , 48 ). A bacterial solution equivalent to a 0.5 McFarland standard was prepared and diluted in MRS broth (for Lactobacillus strains) and BHIS broth (for Bacteroides and Bifidobacterium species) or TSB (for strains of Enterococcus ) to achieve a bacterial concentration of ~5 × 10 5 CFU/mL.…”

Substituted salicylic acid analogs offer improved potency against multidrug-resistant Neisseria gonorrhoeae and good selectivity against commensal vaginal bacteria

“…The MICs of salicylic acid analogs against representative commensal members of the genitourinary tract were determined, as described elsewhere 16 , 45 , 49 – 52 . Lactobacilli were grown onto MRS agar for 48 h at 37 °C in presence of 5% CO 2 .…”