VT-1161—A Tetrazole for Management of Mono- and Dual-Species Biofilms

Abstract

VT-1161 is a novel tetrazole antifungal agent with high specificity for fungal CYP51 (compared to human CYP enzymes) which has been proven to have fewer adverse effects and drug–drug interaction profiles due to fewer off-target inhibitors. In this study, we evaluated the anti-biofilm potential of VT-1161 against mono- and dual-species biofilms of Candida albicans, Klebsiella pneumoniae and Staphylococcus aureus. VT-1161 inhibited planktonic growth of all three strains, with an MIC value of 2 µg mL−1 for C. albicans and 0.5 µg mL−1 for K. pneumoniae and S. aureus, and killed 99.9% of the microbial populations, indicating a cytocidal action. Additionally, VT-1161 showed an excellent anti-biofilm action, since it inhibited mono-microbial biofilms by 80% at 0.5 µg mL−1, and dual-species biofilms of C. albicans/K. pneumoniae and C. albicans/S. aureus by 90% at the same concentration. Additionally, the eradication of mature biofilms after 24 h of VT-1161 exposure was excellent, reaching 90% at 2 μg mL−1 for both mono- and dual-species biofilms. In such mixed biofilms, the use of VT-1161 was revealed to be an alternative treatment because it was able to reduce the number of cells of each species during both inhibition and eradication. Since long-term therapy is necessary for most fungal biofilm infections due to their recurrence and obstinacy, VT-1161 showed low cytotoxicity against normal human cell lines and also against the invertebrate model Caenorhabditis elegans. Considering the excellent anti-biofilm potential and its GRAS (generally recognized as safe) status, VT-1161 may find use in the prevention or therapeutic treatment of mono- or poly-microbial biofilms.

A Preliminary Evaluation on the Antifungal Efficacy of VT-1161 against Persister Candida albicans Cells in Vulvovaginal Candidiasis

“…Then, we followed the development of a new biofilm derived from persisters in the microwell plate model, showing how persisters can progressively develop a new biofilm in situ, mimicking the recolonization of a surface, which may be responsible for recurrent infections. In our previous study [24], we demonstrated that the new azole VT-1161 was able to inhibit and eradicate mono-and polymicrobial biofilms made of fungal/bacterial cells often found in recurrent infections, and here we confirmed the strong ability of VT-1161 to eradicate a secondary biofilm.…”

“…The eradication activity of VT-1161 was evaluated by exposing B2 for 24 h to different concentrations of VT-1161 0.5, 1.0, and 2.0 µg mL −1 and the residual biomass quantified by crystal violet assay, as previously described [24]. The percentage of eradication was calculated as biofilm reduction % = (OD 570 control − OD 570 sample/OD 570 control) × 100, where OD 570 control and OD 570 sample corresponded to the untreated and treated biofilm, respectively.…”

“…VT-1161 was shown to exhibit potent in vitro activity against C. albicans in initial tests and against fluconazole-resistant C. albicans from acute and recurrent vulvovaginal candidiasis [23]. VT-1161 has proved to be clinically effective and safe not only in a phase 2 study in women with recurrent vulvovaginal candidiasis (RVVC) but also in a phase 3 study on the treatment of culture-verified vulvovaginal candidiasis (VVC) episodes, thus leading to its approval by the FDA in April 2022 (clinicaltrials.gov identifier NCT03840616, NCT03562156, NCT03561701) [24].…”

“…In our previous work, we tested the efficacy of VT-1161 as an antibiofilm agent, showing its ability to inhibit and eradicate mono-and dual-species Candida biofilms [24].…”

Antifungals: From Pharmacokinetics to Clinical Practice

“…VIOLET, a phase 3 multicenter, randomized, double-blind, placebo-controlled trial was designed to evaluate oteseconazole efficacy in the treatment of recurrent vulvovaginal candidiasis up to Week 48, the time to first recurrence, safety and patient outcomes. The study concluded that oteseconazole was effective in preventing acute vulvovaginal candidiasis recurrence and treating recurrent vulvovaginal candidiasis in the CL-011 and CL-012 trials, with reduced adverse effects [73,154,155].…”