isobavachalcone

Antibiotic resistance poses a considerable worldwide concern, particularly in clinical environments where drug-resistant Gram-negative bacteria like Klebsiella pneumoniae (K. pneumoniae) present a major challenge. The objective of this research was to investigate the mechanisms by which isobavachalcone (IBC) restores the sensitivity of K. pneumoniae to colistin in vitro and to validate the synergistic therapeutic effect in vivo.

The results indicate that the combined administration of colistin and IBC exhibits a potent antibacterial effect both in vitro and in vivo. The in vitro concurrent administration of colistin and IBC resulted in increased membrane permeability, compromised cell integrity, diminished membrane fluidity, and disrupted membrane homeostasis. Additionally, this combination reduced biofilm production, inhibited the synthesis of the autoinducer factor, altered membrane potential, and affected levels of reactive oxygen species and adenosine triphosphate synthesis, ultimately leading to bacterial death. In vivo experiments on Galleria mellonella and mice demonstrated that the co-administration of colistin and IBC increased the survival rate and significantly reduced pathological damage compared to colistin alone.

These results suggested that IBC effectively restores the sensitivity of colistin by inducing physical disruption of bacterial membranes and oxidative stress. The combination therapy of colistin and IBC presents a viable and safe strategy to combat drug-resistant K. pneumoniae-associated infections.

The fungus Candida albicans causes various kinds of human infections, including oral thrush, vulvovaginitis and life-endangering bloodstream infections, the incidence of which are rising. Worsening this, the clinical antifungals are limited to a few, highlighting the necessity to develop novel antifungal therapies. In this study, the antifungal activities of isobavachalcone against C. albicans SC5314 and nine C. albicans clinical isolates were tested. The effects of isobavachalcone (IBC) on C. albicans virulence factors, such as hyphal formation, adhesion, biofilm formation and extracellular phospholipase production, as well as the underlying mechanism, were also evaluated. Antifungal susceptibility test revealed that IBC has significant anti-Candida activities, with both MIC and MFC being 4-5 μg/mL against all strains tested. Hyphal formation in RPMI-1640, Spider and GlcNAc medium, adhesion to abiotic polystyrene surfaces and surfaces of A549 cells, could be inhibited by IBC. Most important, IBC could inhibit the C. albicans biofilm formation and development. PI staining tests showed that IBC could increase the cell membrane permeability, suggesting the damages to the fungal cell membrane. IBC was further demonstrated to induce excessive ROS production in C. albicans planktonic cells and its mature biofilms, as revealed by DCFH fluorescence detection through flowcytometry and relative fluorescence intensity analysis (with a microplate reader). The roles of ROS in the antifungal activity of IBC were further confirmed through antioxidant rescue assays in MIC and biofilm formation tests. Compared to its antifungal activity, the cytotoxicity against mammalian cells was low, indicating its potential in developing antifungal therapies.