Progression of the late-stage divisome is unaffected by the depletion of the cytoplasmic FtsZ pool

Abstract

Cell division is a central and essential process in most bacteria, and also due to its complexity and highly coordinated nature, it has emerged as a promising new antibiotic target pathway in recent years. We have previously shown that ADEP antibiotics preferably induce the degradation of the major cell division protein FtsZ, thereby primarily leading to a depletion of the cytoplasmic FtsZ pool that is needed for treadmilling FtsZ rings. To further investigate the physiological consequences of ADEP treatment, we here studied the effect of ADEP on the different stages of the FtsZ ring in rod-shaped bacteria. Our data reveal the disintegration of early FtsZ rings during ADEP treatment in Bacillus subtilis, indicating an essential role of the cytoplasmic FtsZ pool and thus FtsZ ring dynamics during initiation and maturation of the divisome. However, progressed FtsZ rings finalized cytokinesis once the septal peptidoglycan synthase PBP2b, a late-stage cell division protein, colocalized at the division site, thus implying that the concentration of the cytoplasmic FtsZ pool and FtsZ ring dynamics are less critical during the late stages of divisome assembly and progression.

Antibiotic Acyldepsipeptides Stimulate the Streptomyces Clp-ATPase/ClpP Complex for Accelerated Proteolysis

“…Second, ADEP binding induces an opening of the ClpP entrance pores and allosterically activates the catalytic centers, thereby allowing access of nonnative substrates to the ClpP degradation chamber that are efficiently degraded ( 19 , 30 , 34 , 35 , 38 , 51 , 52 ). The latter activation of the independent proteolytic core ClpP is the primary cause of bacterial killing in species harboring nonessential ClpP proteins, such as B. subtilis or S. aureus ( 27 , 29 , 30 , 51 , 53 , 54 ). However, in an infection situation, where the Clp protease is essential for the expression of important virulence factors, inhibition of the natural functions will also attenuate a pathogen in the host environment ( 55 , 56 ).…”

Reprogramming of the Caseinolytic Protease by ADEP Antibiotics: Molecular Mechanism, Cellular Consequences, Therapeutic Potential

“…In contrast, mature FtsZ rings, marked by arrival of the peptidoglycan synthases to the division site, were stable and capable of concluding the cell division cycle. The result suggests that the dynamics of FtsZ ring play a minor role in the late stages of divisome progression ( Silber et al, 2021 ).…”

“…Furthermore, the ADEP-triggered “chemical FtsZ knockdown” can be easily combined with other genetically induced cell division mutations. The finding that ADEP-activated ClpP preferably targets FtsZ in the nucleotide-free state at low ADEP concentrations (see Substrates of Acyldepsipeptide-Activated ClpP ) was exploited in a recent study on FtsZ ring formation and progression in B. subtilis ( Silber et al, 2021 ). ADEP primarily leads to the depletion of nucleotide-free monomeric FtsZ from the cytoplasmic pool, which is required for FtsZ ring dynamics.…”