Abstract
In Bacillus licheniformis 749/I, BlaP β-lactamase is induced by the presence of a β-lactam antibiotic outside the cell. The first step in the induction mechanism is the detection of the antibiotic by the membrane-bound penicillin receptor BlaR1 that is composed of two functional domains: a carboxy-terminal domain exposed outside the cell, which acts as a penicillin sensor, and an amino-terminal domain anchored to the cytoplasmic membrane, which works as a transducer-transmitter. The acylation of BlaR1 sensor domain by the antibiotic generates an intramolecular signal that leads to the activation of the L3 cytoplasmic loop of the transmitter by a single-point cleavage. The exact mechanism of L3 activation and the nature of the secondary cytoplasmic signal launched by the activated transmitter remain unknown. However, these two events seem to be linked to the presence of a HEXXH zinc binding motif of neutral zinc metallopeptidases. By different experimental approaches, we demonstrated that the L3 loop binds zinc ion, belongs to Gluzincin metallopeptidase superfamily and is activated by self-proteolysis.
Highlights
During evolution, the most common resistance mechanism acquired by eubacteria to resist b-lactam antibiotic action is the production of a b-lactamase that degrades these antibiotics by opening their b-lactam ring [1,2]
A multiple sequence alignment of BlaR1/MecR N-terminal domains of B. licheniformis and S. aureus (Figure 2) revealed 32 strictly conserved residues in the three aligned sequences corresponding to 9.4% of identity when the length of B. licheniformis BlaR-NTD sequence is used as reference ([34/339]6100 = 9.4%)
Thermolysin is considered as the canonical enzyme of this protease family, its catalytically essential zinc ion is coordinated by the two histidine residues of the motif (H142EXXH, mature thermolysin numbering), the E166 and a water molecule
Summary
The most common resistance mechanism acquired by eubacteria to resist b-lactam antibiotic action is the production of a b-lactamase that degrades these antibiotics by opening their b-lactam ring [1,2]. The cleaved antibiotic is unable to acylate its membrane-bound D,D-peptidase targets, which are involved in the peptidoglycan cross-linking or remodeling. These enzymes inhibited by b-lactam antibiotics are named penicillin-binding proteins (PBPs). In Bacillus licheniformis and Staphylococcus aureus, the production of an inducible class A b-lactamase, BlaP and BlaZ respectively, is regulated by the BlaI repressor that maintains b-lactamase production at a low level in the absence of a b-lactam antibiotic outside the cell. The regulatory genes, blaI and blaR1 are located downstream the blaP/ blaZ genes and are divergently transcribed as a polycistronic mRNA [6]
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