Abstract
Antimicrobial peptides (AMPs) have potential antifungal activities; however, their intracellular protein targets are poorly reported. Proteome microarray is an effective tool with high-throughput and rapid platform that systematically identifies the protein targets. In this study, we have used yeast proteome microarrays for systematical identification of the yeast protein targets of Lactoferricin B (Lfcin B) and Histatin-5. A total of 140 and 137 protein targets were identified from the triplicate yeast proteome microarray assays for Lfcin B and Histatin-5, respectively. The Gene Ontology (GO) enrichment analysis showed that Lfcin B targeted more enrichment categories than Histatin-5 did in all GO biological processes, molecular functions, and cellular components. This might be one of the reasons that Lfcin B has a lower minimum inhibitory concentration (MIC) than Histatin-5. Moreover, pairwise essential proteins that have lethal effects on yeast were analyzed through synthetic lethality. A total of 11 synthetic lethal pairs were identified within the protein targets of Lfcin B. However, only three synthetic lethal pairs were identified within the protein targets of Histatin-5. The higher number of synthetic lethal pairs identified within the protein targets of Lfcin B might also be the reason for Lfcin B to have lower MIC than Histatin-5. Furthermore, two synthetic lethal pairs were identified between the unique protein targets of Lfcin B and Histatin-5. Both the identified synthetic lethal pairs proteins are part of the Spt-Ada-Gcn5 acetyltransferase (SAGA) protein complex that regulates gene expression via histone modification. Identification of synthetic lethal pairs between Lfcin B and Histatin-5 and their involvement in the same protein complex indicated synergistic combination between Lfcin B and Histatin-5. This hypothesis was experimentally confirmed by growth inhibition assay.
Highlights
Treatment of cancer and bacterial infection, as well as immunocompromised patients, has often resulted in fungal infection
Within the protein targets of Histatin-5, we identified a total of three synthetic lethal pairs
The two synthetic lethal pairs identified between the unique protein targets of Lactoferricin B (Lfcin B) and Histatin-5 ensure additional synthetic lethal effects on yeast growth that are not observed with individual treatment of Lfcin B or Histatin-5
Summary
Treatment of cancer and bacterial infection, as well as immunocompromised patients, has often resulted in fungal infection. The identified yeast protein targets of Lfcin B and Histatin-5 were subjected to bioinformatics analysis to identify functional enrichment in gene ontology (GO) and analysis of synthetic lethal pairs. Lfcin B showed unique enrichment in the organization of cytoskeletal structures comprised of actin filaments, such as “actin filament organization”, “regulation of actin filament-based process”, and “actin filament-based process” as well as “cellular component assembly” This over-representation of Lfcin B protein targets shows the possible mechanism of Lfcin B entry inside the yeast and hamper their cytoskeleton. The unique over-representation for the protein targets of Histatin-5 was only observed in two biological processes, i.e., “cellular catabolic process” and “translational initiation” These two categories are related to the breakdown of substances and formation of an initial translational complex of the ribosome, mRNA, respectively. Lfcin B causes higher effect against yeast than that of E. coli
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