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PMID:21969594

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Citation

Sass, P, Josten, M, Famulla, K, Schiffer, G, Sahl, HG, Hamoen, L and Brötz-Oesterhelt, H (2011) Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc. Natl. Acad. Sci. U.S.A. 108:17474-9

Abstract

The worldwide spread of antibiotic-resistant bacteria has lent urgency to the search for antibiotics with new modes of action that are devoid of preexisting cross-resistances. We previously described a unique class of acyldepsipeptides (ADEPs) that exerts prominent antibacterial activity against Gram-positive pathogens including streptococci, enterococci, as well as multidrug-resistant Staphylococcus aureus. Here, we report that ADEP prevents cell division in Gram-positive bacteria and induces strong filamentation of rod-shaped Bacillus subtilis and swelling of coccoid S. aureus and Streptococcus pneumoniae. It emerged that ADEP treatment inhibits septum formation at the stage of Z-ring assembly, and that central cell division proteins delocalize from midcell positions. Using in vivo and in vitro studies, we show that the inhibition of Z-ring formation is a consequence of the proteolytic degradation of the essential cell division protein FtsZ. ADEP switches the bacterial ClpP peptidase from a regulated to an uncontrolled protease, and it turned out that FtsZ is particularly prone to degradation by the ADEP-ClpP complex. By preventing cell division, ADEP inhibits a vital cellular process of bacteria that is not targeted by any therapeutically applied antibiotic so far. Their unique multifaceted mechanism of action and antibacterial potency makes them promising lead structures for future antibiotic development.

Links

PubMed PMC3198362 Online version:10.1073/pnas.1110385108

Keywords

Anti-Bacterial Agents/chemistry; Anti-Bacterial Agents/pharmacology; Bacillus subtilis/cytology; Bacillus subtilis/drug effects; Bacillus subtilis/metabolism; Bacterial Proteins/metabolism; Cell Division/drug effects; Cytoskeletal Proteins/metabolism; Drug Resistance, Bacterial; Endopeptidase Clp/metabolism; Enzyme Activation/drug effects; Oligopeptides/chemistry; Oligopeptides/pharmacology; Staphylococcus aureus/cytology; Staphylococcus aureus/drug effects; Staphylococcus aureus/metabolism; Streptococcus pneumoniae/cytology; Streptococcus pneumoniae/drug effects; Streptococcus pneumoniae/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

STAAW:CLPP

GO:0008462: endopeptidase Clp activity

ECO:0000315:

F

Figure 2 shows septum formation inhibition in those wild type species treated with antibiotic, in mutant clp species septum formation is able to occur even when treated with an antibiotic.

complete
CACAO 4297


See also

References

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