Underlying mechanisms of the effect of minocycline against Candida albicans biofilms

Abstract

Minocycline (MH) is a broad-spectrum antimicrobial agent and semisynthetic tetracycline derivative, which has been widely used in the clinic due to its efficacy. Having the strongest anti-microbial effect, MH exceeded the traditional scope of antibiotics and its previously unknown antifungal activity is also gradually being discovered. To preliminarily investigate the inhibitory effect of MH on Candida albicans ( C. albicans ), changes of cell growth, hyphal formation and transition, biofilm production and signaling pathway gene expression of C. albicans in the presence of MH were assessed in the present study. An XTT reduction assay was performed to quantitatively detect the metabolic activity of biofilms and evaluate the inhibition of MH on this. The results suggested that biofilm formation was clearly inhibited by 67% (P<0.0001) in the presence of 250 µg/ml MH, while mature biofilms were not significantly affected. In addition, MH inhibited the transition from yeast to hypha in a dose-dependent manner. Furthermore, reverse transcription-quantitative PCR revealed that several hyphae- and adhesion-specific genes associated with the Ras/cyclic (c)AMP/protein kinase A (PKA) pathway were differentially expressed following MH treatment, including downregulation of ras family GTPase ( RAS1 ), adenylyl cyclase-associated protein 1 ( CAP1 ), thiamin pyrophosphokinase 1 ( TPK1 ), adenylate cyclase ( CDC35 ), transcription factor (TEC1), agglutinin-like protein 3 ( ALS3 ) and hyphal wall protein 1 ( HWP1 ) and upregulation of EFG1 (enhanced filamentous growth protein 1 gene) and PDE2 (high-affinity phosphodiesterase gene). The most obviously changed genes were TPK1 , HWP1 and RAS1 , downregulated by 0.33-, 0.48- and 0.55-fold, respectively. It was suggested that MH is associated with alterations in the morphology of C. albicans , such as the repression of hypha and biofilm formation of cells, and MH affected the Ras/cAMP pathway to regulate the expression of cAMP-associated genes.

Sarecycline Demonstrated Reduced Activity Compared to Minocycline against Microbial Species Representing Human Gastrointestinal Microbiota

“…Furthermore, the use of broad-spectrum antibiotics has been linked to the emergence of Candida-resistant strains which might cause life-threatening bloodstream infection in susceptible patients [78]. Similar findings have been reported with doxycycline and minocycline [35].…”

“…The aim of this study was to evaluate the effect of sarecycline compared to minocycline on representative microbiota (both bacteria and fungi) commonly found in the human gastrointestinal tract using an in-vitro approach. Importantly, although antibiotics are known to have minimal impact on fungi, our data showed that minocycline have inhibitory activity against Candida [35]. Based on this, we include 4 different Candida species in our study comparing minocycline and sarecycline.…”