SYM-19-04: Melbourne Protein Group Lecture

Inhibition of an essential enzyme involved in cell wall and protein syntheses

TP Soares Da Costa1, CK Gardhi2, CJ Hall1, AR Gendall3, BM Abbott2 and MA Perugini1

  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia
  2. Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia
  3. Department of Animal, Plant and Soil Sciences, AgriBio, Centre for AgriBiosciences, La Trobe University, Victoria 3086, Australia

Dihydrodipicolinate synthase (DHDPS) catalyses the rate limiting step in the diaminopimelate pathway of bacteria and plants. This pathway yields meso-diaminopimelate and lysine, which are essential building blocks for the synthesis of cell wall and housekeeping proteins. Given the essentiality of DHDPS in bacteria and plants, and its absence in humans, this enzyme represents a promising, yet unexplored, antibiotic and herbicide target. We have recently conducted a high throughput chemical screen (HTCS) targeting bacterial DHDPS using a library of 87,648 drug-like compounds. The HTCS yielded a series of micromolar inhibitors, including a promising hit that has subsequently been developed to generate a series of structurally-related analogues. Using a combination of enzyme kinetics, microscale thermophoresis and viability assays, these analogues have been shown to bind and inhibit both Gram-negative and Gram-positive bacterial DHDPS in vitro, and possess bacteriocidal activity in vivo without showing toxicity to human cells. Interestingly, the analogues also have broad spectrum activity against plant DHDPS.In planta assays indicate that these compounds are able to inhibit germination and growth of Arabidopsis thaliana in a comparative manner to the herbicide, glyphosate. This study provides proof-of-concept that a new class of broad spectrum antimicrobials and herbicides can be developed targeting the essential bacterial and plant enzyme, DHDPS.