A Label-Free Cellular Proteomics Approach to Decipher the Antifungal Action of DiMIQ, a Potent Indolo[2,3-b]Quinoline Agent, against Candida albicans Biofilms

Abstract

Candida albicans forms extremely drug-resistant biofilms, which present a serious threat to public health globally. Biofilm-based infections are difficult to treat due to the lack of efficient antifungal therapeutics, resulting in an urgent demand for the development of novel antibiofilm strategies. In this study, the antibiofilm activity of DiMIQ (5,11-dimethyl-5H-indolo[2,3-b]quinoline) was evaluated against C. albicans biofilms. DiMIQ is a synthetic derivative of indoquinoline alkaloid neocryptolepine isolated from a medicinal African plant, Cryptolepis sanguinolenta. Antifungal activity of DiMIQ was determined using the XTT assay, followed by cell wall and extracellular matrix profiling and cellular proteomes. Here, we demonstrated that DiMIQ inhibited C. albicans biofilm formation and altered fungal cell walls and the extracellular matrix. Cellular proteomics revealed inhibitory action against numerous translation-involved ribosomal proteins, enzymes involved in general energy producing processes and select amino acid metabolic pathways including alanine, aspartate, glutamate, valine, leucine and isoleucine. DiMIQ also stimulated pathways of cellular oxidation, metabolism of carbohydrates, amino acids (glycine, serine, threonine, arginine, phenylalanine, tyrosine, tryptophan) and nucleic acids (aminoacyl-tRNA biosynthesis, RNA transport, nucleotide metabolism). Our findings suggest that DiMIQ inhibits C. albicans biofilms by arresting translation and multidirectional pathway reshaping of cellular metabolism. Overall, this agent may provide a potent alternative to treating biofilm-associated Candida infections.

Inhibitory Effects of the Fungal Pigment Rubiginosin C on Hyphal and Biofilm Formation in Candida albicans and Candida auris

“…In line with this observation, Rub W, which differs in the number of carbon atoms in the side chain, was less effective than Rub C. It is likely that more lipophilic compounds can penetrate biological membranes more easily [50]. As a result, lipophilic compounds may have better access to their target sites within the cell, leading to enhanced activity [51,52]. In the case of Rub C, the structure of the side chain resembles to some degree that of FA.…”

Exposure of Candida parapsilosis to the silver(I) compound SBC3 induces alterations in the proteome and reduced virulence

“…Therefore, it has been applied to provide insight on the effect(s) of novel and conventional antifungal treatments. 105 – 108 The results presented here indicate that exposure of C. parapsilosis to SBC3 results in reductions in proteins associated with protein synthesis, amino acid synthesis, and respiration and in virulence as measured by the inhibition of adherence and biofilm formation. These findings provide a novel insight into the mode of action of SBC3 and encourage further research into this interesting antifungal agent.…”