Fluorogenic Probes/Inhibitors of β‐Lactamase and their Applications in Drug‐Resistant Bacteria

Abstract

Abstractβ‐Lactam antibiotics are generally perceived as one of the greatest inventions of the 20th century, and these small molecular compounds have saved millions of lives. However, upon clinical application of antibiotics, the β‐lactamase secreted by pathogenic bacteria can lead to the gradual development of drug resistance. β‐Lactamase is a hydrolase that can efficiently hydrolyze and destroy β‐lactam antibiotics. It develops and spreads rapidly in pathogens, and the drug‐resistant bacteria pose a severe threat to human health and development. As a result, detecting and inhibiting the activities of β‐lactamase are of great value for the rational use of antibiotics and the treatment of infectious diseases. At present, many specific detection methods and inhibitors of β‐lactamase have been developed and applied in clinical practice. In this Minireview, we describe the resistance mechanism of bacteria producing β‐lactamase and further summarize the fluorogenic probes, inhibitors of β‐lactamase, and their applications in the treatment of infectious diseases. It may be valuable to design fluorogenic probes with improved selectivity, sensitivity, and effectiveness to further identify the inhibitors for β‐lactamases and eventually overcome bacterial resistance.

Drugs That Changed Society: History and Current Status of the Early Antibiotics: Salvarsan, Sulfonamides, and β-Lactams

“…These enzymes efficiently neutralize penicillins by opening the β-lactam ring to give penicilloic acid ( 33 ). Cleavage of the β-lactam ring removes the antibacterial effect [ 43 , 52 , 72 ]. In principle, this is the same acylation of a serine residue that occurs, when penicillins inactivates penicillin-binding proteins.…”

“…In several pathogenic organisms, expression of β-lactamases is provoked by β-lactam antibiotics [ 76 ]. The β-lactamases are divided into three classes A (penicillin-hydrolyzing), C (cephalosporin-hydrolyzing) and D (oxacillin-hydrolyzing) and Class B the metallo-β-lactamases [ 44 , 70 , 72 , 77 ]. Class C are primarily found in Gram-negative bacteria [ 44 ].…”

Click and Release Chemistry for Activity‐Based Purification of β‐Lactam Targets

“…This limitation has been addressed by the use of biotinylated azido‐containing dyes for streptavidin affinity pull‐down purification followed by mass spectrometry analysis [15,16] . Selective penicillin‐binding protein imaging probes have also been described using fluorescent β‐lactams, [17] such as fluorescent cephalosporins [18] . Of note, fluorescent β‐lactams were also used as fluorogenic molecular probes for the detection of β‐lactamases in vitro or in living bacteria [17,19,20] …”

“…Selective penicillin‐binding protein imaging probes have also been described using fluorescent β‐lactams, [17] such as fluorescent cephalosporins [18] . Of note, fluorescent β‐lactams were also used as fluorogenic molecular probes for the detection of β‐lactamases in vitro or in living bacteria [17,19,20] …”

“…[18] Of note, fluorescent β-lactams were also used as fluorogenic molecular probes for the detection of β-lactamases in vitro or in living bacteria. [17,19,20] In this study, we explore a strategy for combined affinity purification and fluorescence labeling of carbapenem targets. We report synthetic routes to alkynylated carbapenems that effectively labeled a model L,D-transpeptidase (Ldt fm ) both with respect to the kinetics of acylation and the stability of the resulting acylenzymes.…”