Abstract
Production of beta-lactamases, the enzymes that degrade beta-lactam antibiotics, is the most widespread and threatening mechanism of antibiotic resistance. In the past, extensive research has focused on the structure, function, and ecology of beta-lactamases while limited efforts were placed on the regulatory mechanisms of beta-lactamases. Recently, increasing evidence demonstrate a direct link between beta-lactamase induction and cell wall metabolism in Gram-negative bacteria. Specifically, expression of beta-lactamase could be induced by the liberated murein fragments, such as muropeptides. This article summarizes current knowledge on cell wall metabolism, beta-lactam antibiotics, and beta-lactamases. In particular, we comprehensively reviewed recent studies on the beta-lactamase induction by muropeptides via two major molecular mechanisms (the AmpG–AmpR–AmpC pathway and BlrAB-like two-component regulatory system) in Gram-negative bacteria. The signaling pathways for beta-lactamase induction offer a broad array of promising targets for the discovery of new antibacterial drugs used for combination therapies. Therefore, to develop effective mitigation strategies against the widespread beta-lactam resistance, examination of the molecular basis of beta-lactamase induction by cell wall fragment is highly warranted.
Highlights
Bacteria should continuously maintain and shape their envelopes to adapt enormous stresses they encounter in different niches and to meet physiological needs, such as growth and multiplication
In Gramnegative bacteria, the beta-lactamase was usually produced at very high concentration constitutively or by induction via direct interaction of beta-lactam antibiotic with regulatory system (e.g., MecR1/MecI in Staphylococcus aureus; Kogut et al, 1956; Richmond, 1963, 1965; Pollock, 1965; Zhu et al, 1992; Fuda et al, 2005; Safo et al, 2005)
Given the lack of information on the relationship between beta-lactamase induction and cell wall metabolism in Gram-positive bacteria, in this review, we only summarize the relevant background information and recent research on the mechanisms of beta-lactamase induction by cell wall fragments in Gram-negative bacteria
Summary
Production of beta-lactamases, the enzymes that degrade beta-lactam antibiotics, is the most widespread and threatening mechanism of antibiotic resistance. Increasing evidence demonstrate a direct link between beta-lactamase induction and cell wall metabolism in Gram-negative bacteria. This article summarizes current knowledge on cell wall metabolism, beta-lactam antibiotics, and beta-lactamases. We comprehensively reviewed recent studies on the beta-lactamase induction by muropeptides via two major molecular mechanisms (the AmpG–AmpR–AmpC pathway and BlrAB-like two-component regulatory system) in Gram-negative bacteria. The signaling pathways for beta-lactamase induction offer a broad array of promising targets for the discovery of new antibacterial drugs used for combination therapies. To develop effective mitigation strategies against the widespread beta-lactam resistance, examination of the molecular basis of beta-lactamase induction by cell wall fragment is highly warranted
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