GSE209674
The unusual mode of action of the polyketide glycoside antibiotic cervimycin C [I]
The resistance to antibiotics is an emerging problem, and necessitates novel antibacterial therapies. Cervimycins A–D are bi-glycosylated polyketides produced by Streptomyces tendae HKI 0179 with promising activity against Gram-positive bacteria. Microscopically, cervimycin C (CmC) treatment caused a spaghetti-like phenotype in Bacillus subtilis 168, with elongated curved cells, which stayed joined after cell division, and exhibited a chromosome segregation defect. Electron microscopy of cervimycin treated S. aureus revealed swelling of some cells, misshaped septa, and cell wall thickening and a rough cell wall surface. Incorporation tests in B. subtilis indicated an effect on DNA metabolism at high cervimycin-concentrations. Indeed, the down-regulation of the DNA gyrase subunit B (gyrB) acted synergistically with cervimycin, and the antibiotic inhibited the in vitro DNA gyrase supercoiling activity. To get a more global view on the mode of action of CmC, transcriptomics and proteomics of cervimycin treated versus untreated S. aureus cells were performed. Interestingly, and in contrast to the previous results, cervimycin did not induce the SOS response in S. aureus, which would indicate disturbance of the DNA gyrase. Instead, cervimycin induced the expression of the CtsR/HrcA heat shock operon and the expression of autolysins. Taken together, we identified the DNA gyrase as one target of cervimycin, but omics data revealed massive alterations in cervimycin treated S. aureus, involving cell wall modifying enzymes and protein stress response, indicating a complex mode of action of cervimycin, that is distinct from other antibiotics. Overall design: Comparative gene expression profiling analysis of RNA-seq data for S. aureus SG511 cells treated with three-times minimal inhibitory concentration cervimycin C versus untreated cells.