Evolution of Drug Resistance: Insight on TEM β-Lactamases Structure and Activity and β-Lactam Antibiotics

Abstract

Since the discovery of the first penicillin bacterial resistance to β-lactam antibiotics has spread and evolved promoting new resistances to pathogens. The most common mechanism of resistance is the production of β-lactamases that have spread thorough nature and evolve to complex phenotypes like CMT type enzymes. New antibiotics have been introduced in clinical practice, and therefore it becomes necessary a concise summary about their molecular targets, specific use and other properties. β-lactamases are still a major medical concern and they have been extensively studied and described in the scientific literature. Several authors agree that Glu166 should be the general base and Ser70 should perform the nucleophilic attack to the carbon of the carbonyl group of the β-lactam ring. Nevertheless there still is controversy on their catalytic mechanism. TEMs evolve at incredible pace presenting more complex phenotypes due to their tolerance to mutations. These mutations lead to an increasing need of novel, stronger and more specific and stable antibiotics. The present review summarizes key structural, molecular and functional aspects of ESBL, IRT and CMT TEM β-lactamases properties and up to date diagrams of the TEM variants with defined phenotype. The activity and structural characteristics of several available TEMs in the NCBI-PDB are presented, as well as the relation of the various mutated residues and their specific properties and some previously proposed catalytic mechanisms.

Nosocomial infection and its molecular mechanisms of antibiotic resistance

“…Those mutations, which change the ESBLs phenotype transform the configuration of the active site of the enzyme, and allow interaction between active site and oxyimino-β-lactams (18)(19)(20). Exposing the active site to β-lactam substrates also leads to susceptibility of the ESBLs to β-lactamase inhibitors, such as clavulanic acid.…”

A Triple Mutant in the Ω-loop of TEM-1 β-Lactamase Changes the Substrate Profile via a Large Conformational Change and an Altered General Base for Catalysis

“…TEM-1 ␤-lactamase is a plasmid-encoded, class A enzyme with high catalytic efficiency (k cat/ K m ) for the hydrolysis of penicillins and early cephalosporins but not oxyimino-cephalosporins such as ceftazidime (8,9). The extensive use of oxyimino-cephalosporins has led to the emergence of variants of TEM-1 that can more efficiently hydrolyze these drugs.…”

15N, 13C and 1H backbone resonance assignments of an artificially engineered TEM-1/PSE-4 class A β-lactamase chimera and its deconvoluted mutant

“…This class of hydrolases, comprising hundreds of members, is specific for β-lactam compounds such as penicillins and cephalosporins (Pimenta et al 2014). The class A β-lactamase TEM-1 has been extensively characterized.…”