In vitro inhibitors of Candida albicans biofilms: A systematic review and meta-analysis of multi-target mechanisms.

Candida albicans biofilms are intrinsically tolerant to antifungals due to coordinated regulation of hyphal morphogenesis, adhesins/matrix, and sterol biosynthesis. We conducted a PRISMA 2020-guided in vitro systematic review restricted to full-text-assessed studies (18 studies) and a meta-analysis of five studies with extractable quantitative outcomes to estimate pooled inhibition and compare mechanistic classes across natural and synthetic agents. Across the eligible evidence base, effective compounds converged on multi-target pathways, including repression of hyphal transcriptional programs (e.g., EFG1/CPH1/TEC1 axes), interference with adhesins and extracellular matrix integrity (ALS3/HWP1; matrix disruption), and perturbation of ergosterol biosynthesis (e.g., ERG11). Phenotypic readouts consistently included reduced initial adhesion, impaired biofilm maturation, and dispersion/viability loss in mature biofilms. The pooled effect among studies eligible for meta-analysis indicated consistent inhibition (log-odds ratio -2.05; 95% CI -2.60 to -1.51; I² = 60.4%), although inference remains limited by the small number of studies and assay heterogeneity. Evidence is restricted to in vitro C. albicans models; non-albicans outcomes were summarized qualitatively when reported in eligible full-text studies. Quantification suggests that dual targeting of gene regulation and biofilm integrity yields reproducible in vitro inhibition, but future studies should standardize endpoints, report variance measures, validate in vivo and non-albicans taxa, and translate mechanistic readouts to actionable efficacy metrics. LAY SUMMARY: Candida albicans biofilms resist drugs. Across 18 full-text-assessed in vitro studies (with five pooled), diverse compounds reduced biofilms by targeting multiple weak spots - growth programs, adhesion, matrix integrity, and sterols. Promising, but standardized reporting and clinical/in vivo testing are still needed.