Streptomyces: A Screening Tool for Bacterial Cell Division Inhibitors

Abstract

Cell division is essential for spore formation but not for viability in the filamentous streptomycetes bacteria. Failure to complete cell division instead blocks spore formation, a phenotype that can be visualized by the absence of gray (in Streptomyces coelicolor) and green (in Streptomyces venezuelae) spore-associated pigmentation. Despite the lack of essentiality, the streptomycetes divisome is similar to that of other prokaryotes. Therefore, the chemical inhibitors of sporulation in model streptomycetes may interfere with the cell division in rod-shaped bacteria as well. To test this, we investigated 196 compounds that inhibit sporulation in S. coelicolor. We show that 19 of these compounds cause filamentous growth in Bacillus subtilis, consistent with impaired cell division. One of the compounds is a DNA-damaging agent and inhibits cell division by activating the SOS response. The remaining 18 act independently of known stress responses and may therefore act on the divisome or on divisome positioning and stability. Three of the compounds (Fil-1, Fil-2, and Fil-3) confer distinct cell division defects on B. subtilis. They also block B. subtilis sporulation, which is mechanistically unrelated to the sporulation pathway of streptomycetes but is also dependent on the divisome. We discuss ways in which these differing phenotypes can be used in screens for cell division inhibitors.

DNA damage-induced block of sporulation in Streptomyces venezuelae involves downregulation of ssgB

“…To gain insight into the observed effect of DNA damage on the developmental programme leading to the inhibition of sporulation (classically referred to as a 'white phenotype') in Streptomyces (Fig. 1) [26,27], we performed an exploratory RNA-seq experiment to identify global changes in the S. venezuelae transcriptome following the addition of the DNA alkylating agent mitomycin C (MMC). We grew liquid cultures of S. venezuelae for 12 h at which point hyphae were still growing vegetatively, added MMC at the subinhibitory concentration of 0.25 μg ml −1 and extracted RNA from hyphae 0, 20, 40 and 80 min later.…”

Production of bioactive compounds with bactericidal and antioxidant potential by endophytic fungus Alternaria alternata AE1 isolated from Azadirachta indica A. Juss.

“…End to end joining or mycelia nature of E . coli upon treatment indicated an effect of antimicrobial compounds on normal cell division function [31].…”

Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation

“…In this study, we describe the discovery of a gyrase inhibitor, EN-7, from a screen against Streptomyces sporulation septation. We have previously used Streptomyces as a small-molecule screening platform for compounds that affect secondary metabolism (Craney et al., 2012) and sporulation (Jani et al., 2015), which is a form of developmentally controlled cell division. Streptomyces sporulation employs specific genes that drive changes in cell morphology and fate.…”

“…Intriguingly, some of the compounds that target sporulation turned out to have antibacterial effects against rod-shaped and coccoid bacteria, such as Bacillus subtilis and Staphylococcus aureus. These molecules targeted cells in unusual ways that are clearly outside the most common suite of antibiotic targets: one compound blocked septation (Jani et al., 2015) and another interfered with the relationship between cell growth and cell division (McAuley et al., 2019).…”