Inhibitor of Chromosome Segregation in Pseudomonas aeruginosa from Fungal Extracts

• Published in: ACS chemical biology 2024-06, Vol.19 (6), p.1387-1396
• Main Authors: Zhao, Hang, Peramuna, Thilini, Ajmal, Sidra, Wendt, Karen L., Petrushenko, Zoya M., Premachandra, Kaushika, Cichewicz, Robert H., Rybenkov, Valentin V.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Chromosome Segregation - drug effects; Microbial Sensitivity Tests; Pseudomonas aeruginosa - drug effects
• ISSN: 1554-8929; 1554-8937; 1554-8937
• DOI: 10.1021/acschembio.4c00264

Chromosome segregation is an essential cellular process that has the potential to yield numerous targets for drug development. This pathway is presently underutilized partially due to the difficulties in the development of robust reporter assays suitable for high throughput screening. In bacteria, chromosome segregation is mediated by two partially redundant systems, condensins and ParABS. Based on the synthetic lethality of the two systems, we developed an assay suitable for screening and then screened a library of fungal extracts for potential inhibitors of the ParABS pathway, as judged by their enhanced activity on condensin-deficient cells. We found such activity in extracts of Humicola sp. Fractionation of the extract led to the discovery of four new analogues of sterigmatocystin, one of which, 4-hydroxy-sterigmatocystin (4HS), displayed antibacterial activity. 4HS induced the phenotype typical for parAB mutants including defects in chromosome segregation and cell division. Specifically, bacteria exposed to 4HS produced anucleate cells and were impaired in the assembly of the FtsZ ring. Moreover, 4HS binds to purified ParB in a ParS-modulated manner and inhibits its ParS-dependent CTPase activity. The data describe a small molecule inhibitor of ParB and expand the known spectrum of activities of sterigmatocystin to include bacterial chromosome segregation.