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Genetic and biochemical deconvolution of maize antibiotic pathways

ABSTRACT: Specialized metabolites provide important layers of biochemical immunity underlaying crop resistance; however, challenges in resolving pathways limit applications. To understand maize (Zea mays) antibiotics imparting disease resistance we integrated large-scale transcriptomic patterns, association mapping, enzyme assays, proteomics, structure elucidation and targeted mutagenesis. Three zealexin (Zx) gene clusters (GC) comprised of 4 sesquiterpene synthases (GC1:Zx1-4) and 6 cytochrome P450s in the Cyp71Z (GC2:Zx5-7) and Cyp81E (GC3:Zx8-10) families drive the production diverse antibiotic cocktails. Gene duplications ensure pathway resiliency to single null mutations while promiscuous enzymes constitute a biosynthetic hourglass pathway acting on diverse endogenous substrates to drive additional antibiotic complexity. Zx pathway activation mediating pathogen resistance occurs during a dramatic reorganization of >50% of the measurable proteome. Understanding the genetic basis of specialized metabolic pathways structured to maintain disease resistance provides a conceptual foundation for transferring durable biochemical immunity between plants.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Zea Mays (ncbitaxon:4577)

SUBMITTER: Alisa Huffaker

PROVIDER: MSV000084285 | MassIVE |

REPOSITORIES: MassIVE

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic resistant bacterial infections acquired during hospital stays have increased. Instead of designing and deploying new antibiotics which MRSA would quickly develop resistance to, adjuvants are a key strategy to combatting these bacteria. We have evaluated several small molecule adjuvants that have strong potentiation with β-lactam antibiotics and have now investigated at the molecular level how the lead adjuvant exerts its effects. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with a β-lactam antibiotic (oxacillin) and the adjuvant (compound 8). Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up and downregulated, respectively, upon cotreatment with oxacillin and compound 8. We identified four subclusters of genes that were regulated in similar patterns in response to drug treatment. Many of these genes displayed a similar pattern of expression where they were unaffected by compound 8 treatment alone, upregulated upon antibiotic challenge, and downregulated again upon cotreatment. GO categories that were significantly enriched among downregulated genes involved carbohydrate utilization and/or transport. Most of the biochemical pathways enriched with significantly downregulated genes involved carbohydrate utilization, such as the citric acid cycle (p=6.4x10-6) and the phosphotransferase system (p=1.8x10-5). The most populated pathway was S. aureus infection (p=3.0x10-3). Creating a network of affected gene products helped uncover potential master regulators for further investigation. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect. These results point to this adjuvant as having potential broad therapeutic use in combatting MRSA infections.

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Genetic and biochemical deconvolution of maize antibiotic pathways

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