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Harzianic acid exerts antimicrobial activity against Gram-positive bacteria and targets the cell membrane.

ABSTRACT: The thermophilic fungus Oidiodendron flavum is a saprobe that is commonly isolated from soil. Here, we identified a Gram-positive bacteria-selective antimicrobial secondary metabolite from this fungal species, harzianic acid (HA). Using Bacillus subtilis strain 168 combined with dynamic bacterial morphology imaging, we found that HA targeted the cell membrane. To further study the antimicrobial activity of HA, we isolated an HA-resistant strain, Bacillus subtilis strain M9015, and discovered that the mutant had more translucent colonies than the wild type strain, showed cross resistance to rifampin, and harbored five mutations in the coding region of four distinct genes. Further analysis of these genes indicated that the mutation in atpE might be responsible for the translucency of the colonies, and mutation in mdtR for resistance to both HA and rifampin. We conclude that HA is an antimicrobial agent against Gram-positive bacteria that targets the cell membrane.

SUBMITTER: Ouyang X

PROVIDER: S-EPMC10860749 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Harzianic acid exerts antimicrobial activity against Gram-positive bacteria and targets the cell membrane.

Ouyang Xudong X Hoeksma Jelmer J Beenker Wouter A G WAG van der Beek Samantha S den Hertog Jeroen J

Frontiers in microbiology 20240129

The thermophilic fungus Oidiodendron flavum is a saprobe that is commonly isolated from soil. Here, we identified a Gram-positive bacteria-selective antimicrobial secondary metabolite from this fungal species, harzianic acid (HA). Using Bacillus subtilis strain 168 combined with dynamic bacterial morphology imaging, we found that HA targeted the cell membrane. To further study the antimicrobial activity of HA, we isolated an HA-resistant strain, Bacillus subtilis strain M901 ...[more]

PMID: 38348189

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Project description:The rapid evolution of antibiotic resistance is shrinking our stockpile of commercially available antibiotics. Therefore, new antimicrobials with novel mechanisms of action (MoAs) are desperately needed. The free fatty acid, (Z)-13-methyltetra-4-decenoic acid ((Z)-4C-14:1), isolated from a marine sediment bacterium Olleya marilimosa, displays strong inhibition of Gram-positive pathogens with minimal cytotoxic effects to mammalian cells. Here, we applied a combination of experimental approaches to identify the mechanism by which (Z)-4C-14:1 kills the Gram-positive bacterium Bacillus subtilis. Using quick and cost-effective bacterial cytological profiling (BCP), we established the cytological signatures of 17 antibiotics representing 6 general classes of antibiotic MoAs. We used BCP to demonstrate that while (Z)-4C-14:1-treated B. subtilis cells display unique morphological features compared to other antibiotic classes, (Z)-4C-14:1 mode of action shares substantial overlap with the fast-acting antibiotic colistin specifically in Gram-positive cells and daptomycin, both of which target bacterial permeability by destroying the cell membrane and causing extensive cell surface alterations. To further determine if the cell membrane of B. subtilis was the target of (Z)-4C-14:1, we used cell membrane- and peptidoglycan-specific diagnostic stains to investigate bacterial permeability. Our results indicate that (Z)-4C-14:1 destabilizes the cell membrane by pore formation in Gram-positive bacteria and emphasize the importance of mining the marine environment for naturally occurring antibiotics.IMPORTANCEWith the lack of new antibiotics in the drug discovery pipeline, coupled with accelerated evolution of antibiotic resistance, new sources of antibiotics that target pathogens of clinical importance are paramount. Here, we use bacterial cytological profiling to identify the mechanism of action of the monounsaturated fatty acid (Z)-13-methyltetra-4-decenoic acid isolated from the marine bacterium Olleya marilimosa with antibacterial effects against Gram-positive bacteria. The fatty acid antibiotic was found to rapidly destabilize the cell membrane by pore formation and membrane aggregation in Bacillus subtilis, suggesting that this fatty acid may be a promising adjuvant used in combination to enhance antibiotic sensitivity.

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Harzianic acid exerts antimicrobial activity against Gram-positive bacteria and targets the cell membrane.

Publications

Harzianic acid exerts antimicrobial activity against Gram-positive bacteria and targets the cell membrane.

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