Abstract
Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme’s active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM–type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl–enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.
Highlights
The global rise in antibiotic consumption is simultaneously increasing the number of microorganisms that have antimicrobial resistance [1]
The key mechanism of this bacterial resistance type is the hydrolysis of antibiotics by β-lactamases
This review focuses on the structural peculiarities of the Ω-loop of TEM-type βLs—the most versatile group of serine class A enzymes that still remain one of the most common βLs among bacterial clinical pathogens and soil bacteria [16,17]
Summary
The global rise in antibiotic consumption is simultaneously increasing the number of microorganisms that have antimicrobial resistance [1]. The key mechanism of this bacterial resistance type is the hydrolysis of antibiotics by β-lactamases (βLs) Their widespread prevalence is due to the localization of the genes that encode βLs on mobile genetic elements, and, for this reason, they may be quickly transferred between bacteria [4]. ΒLs belong to the superfamily of enzymes that hydrolyze the β-lactam ring, and about 2800 βLs have been isolated and described from clinical bacterial strains [5] These enzymes differ in their structure, catalytical activity, specificity, and resistance to inhibitors. This review focuses on the structural peculiarities of the Ω-loop of TEM-type βLs—the most versatile group of serine class A enzymes that still remain one of the most common βLs among bacterial clinical pathogens and soil bacteria [16,17]. A detailed analysis of the loop is carried out in order to establish its role as a site of the allosteric regulation of activity and the specificity of βLs, as well as a potential target for novel inhibitors
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