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.

Small Molecular Fluorescent Probes: Application Progress of Specific Bacteria Detection and Antibacterial Phototherapy

“…The widespread use of Bla antibiotics not only changes the permeability of bacterial cell walls or membranes to reduce their effectiveness but also produces Bla to destroy antibiotics, leading to the development of antibiotic resistance in pathogens [33] . Therefore, targeting Bla with improved selectivity/sensitivity/effectiveness is of great significance to fluorescently image of super bacteria and further identify inhibitors for Bla for eventually overcoming bacterial resistance [34] . According to the type of substrate, Bla can be divided into penicillin enzyme, cephalosporin enzyme, Extended‐Spectrum β‐Lactamases (ESBLs), and carbapenem enzyme.…”

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“… 17 , 18 , 19 Moreover, the low cost and good safety, as well as the favorable pharmacokinetic properties of PACs, make them attractive antibiotic adjuvant candidates for translational application. Historically, classical β-lactamase inhibitors such as clavulanate, sulbactam, and tazobactam, effectively prevent the hydrolysis of antibiotics by inhibiting β-lactamase activity, 20 which obtain proven success in the clinic over the past decades. Additionally, some progress has been achieved in the development of new antibiotic adjuvants in recent years.…”

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“…Besides, gram‐negative bacteria, including Escherichia coli ( E. coli ), Klebsiella pneumoniae ( K. pneumoniae ), and Enterobacter cloacae ( E. cloacae ), can also develop severe resistance to β‐lactam antibiotics due to their gradual generation of β‐lactamase, and nowadays, their various subtypes have spread all over the world 7,8 . In view of the possibility that the global situation of AMR could become more serious, the detection and identification of drug‐resistant bacteria are particularly important 9–13 …”