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Functional Characterisation of ClpP Mutations Conferring Resistance to Acyldepsipeptide Antibiotics in Firmicutes
Author(s) -
Malik Imran T.,
Pereira Rebeca,
Vielberg MarieTheres,
Mayer Christian,
Straetener Jan,
Thomy Dhana,
Famulla Kirsten,
Castro Helena,
Sass Peter,
Groll Michael,
BrötzOesterhelt Heike
Publication year - 2020
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900787
Subject(s) - bacillus subtilis , microbiology and biotechnology , firmicutes , staphylococcus aureus , mutant , biology , proteolysis , protease , bacteria , antibiotics , proteases , genetics , biochemistry , gene , enzyme , 16s ribosomal rna
Acyldepsipeptide (ADEP) is an exploratory antibiotic with a novel mechanism of action. ClpP, the proteolytic core of the caseinolytic protease, is deregulated towards unrestrained proteolysis. Here, we report on the mechanism of ADEP resistance in Firmicutes. This bacterial phylum contains important pathogens that are relevant for potential ADEP therapy. For Staphylococcus aureus , Bacillus subtilis , enterococci and streptococci, spontaneous ADEP‐resistant mutants were selected in vitro at a rate of 10 −6 . All isolates carried mutations in clpP . All mutated S. aureus ClpP proteins characterised in this study were functionally impaired; this increased our understanding of the mode of operation of ClpP. For molecular insights, crystal structures of S. aureus ClpP bound to ADEP4 were determined. Well‐resolved N‐terminal domains in the apo structure allow the pore‐gating mechanism to be followed. The compilation of mutations presented here indicates residues relevant for ClpP function and suggests that ADEP resistance will occur at a lower rate during the infection process.