CTX-M β-lactamases are considered a paradigm in the evolution of a resistance mechanism. Incorporation of different chromosomal blaCTX-M related genes from different species of Kluyvera has derived in different CTX-M clusters. In silico analyses have shown that this event has occurred at least nine times; in CTX-M-1 cluster (3), CTX-M-2 and CTX-M-9 clusters (2 each), and CTX-M-8 and CTX-M-25 clusters (1 each). This has been mainly produced by the participation of genetic mobilization units such as insertion sequences (ISEcp1 or ISCR1) and the later incorporation in hierarchical structures associated with multifaceted genetic structures including complex class 1 integrons and transposons. The capture of these blaCTX-M genes from the environment by highly mobilizable structures could have been a random event. Moreover, after incorporation within these structures, β-lactam selective force such as that exerted by cefotaxime and ceftazidime has fuelled mutational events underscoring diversification of different clusters. Nevertheless, more variants of CTX-M-enzymes, including those not inhibited by β-lactamase inhibitors such as clavulanic acid (IR-CTX-M variants), only obtained under in in vitro experiments are still waiting to emerge in the clinical setting. Penetration and the later global spread of CTX-M producing organisms have been produced with the participation of the so called “epidemic resistance plasmids” often carried in multidrug resistant and virulent high risk clones. All these facts but also the incorporation and coselection of emerging resistance determinants within CTX-M producing bacteria, such as those encoding carbapenemases, depict the currently complex pandemic scenario of multi-drug resistant isolates.

/pdf/ctx-m-enzymes-origin-and-diffusion-2vhwm45sk3.pdf

CTX-M enzymes: origin and diffusion

https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)61550-0/pdf

The emergence of antibiotic resistance by mutation.

Bacterial resistance is a serious threat to human health The production of β-lactamase, which inactivates β-lactams is most common cause of resistance to the β-lactam antibiotics The Class A enzymes are most frequently encountered among the four β-lactamases in the clinic isolates Mutations in class A β-lactamases play a crucial role in substrate and inhibitor specificity SHV and TEM type are known to be most common class A β-lactamases In the present study, we have analyzed the effect of inhibitor resistant S130G point mutation of SHV type Class-A β-lactamase using molecular dynamics and other in silico approaches Our study involved the use of different in silico methods to investigate the affect of S130G point mutation on the major physico-chemical properties of SHV type class A β-lactamase We have used molecular dynamics approach to compare the dynamic behaviour of native and S130G mutant form of SHV β-lactamase by analyzing different properties like root mean square deviation (RMSD), H-bond, Radius of gyration (Rg) and RMS fluctuation of mutation The results clearly suggest notable loss in the stability of S130G mutant that may further lead to decrease in substrate specificity of SHV Molecular docking further indicates that S130G mutation decreases the binding affinity of all the three inhibitors in clinical practice

/pdf/insight-into-the-effect-of-inhibitor-resistant-s130g-mutant-c5vrbb0ksv.pdf

Insight into the Effect of Inhibitor Resistant S130G Mutant on Physico-Chemical Properties of SHV Type Beta-Lactamase: A Molecular Dynamics Study

CTX-M-25 is a novel extended-spectrum β-lactamase isolated from a single Canadian Escherichia coli isolate. Susceptibility testing demonstrated that this enzyme confers resistance to both cefotaxime and ceftazidime, but the level of resistance was reduced with the addition of β-lactamase inhibitors. The blaCTX-M-25 gene was detected on a 111-kb plasmid. It is a member of the CTX-M-8 group and has the closest amino acid identity (99%; three amino acid substitutions) with CTX-M-26. The blaCTX-M-26 gene was detected on a 100-kb plasmid isolated from a Klebsiella pneumoniae strain from the United Kingdom, and plasmid profiling revealed that it showed some homology to the blaCTX-M-25-harboring plasmid. Both CTX-M genes were located downstream of ISEcp1, although the copy upstream of blaCTX-M-25 was disrupted by IS50-A. Comparative kinetic studies of recombinant CTX-M-25 and CTX-M-26 enzymes showed that CTX-M-25 has a higher level of ceftazidime hydrolysis (kcat values, 33 and 0.005 s−1 for CTX-M-25 and CTX-M-26, respectively).

Molecular and Kinetic Comparison of the Novel Extended-Spectrum β-Lactamases CTX-M-25 and CTX-M-26

The new β-lactamase SHV-72 was isolated from clinical Klebsiella pneumoniae INSRA1229, which exhibited the unusual association of resistance to the amoxicillin-clavulanic acid combination (MIC, 64 μg/ml) and susceptibility to cephalosporins, aztreonam, and imipenem. SHV-72 (pI 7.6) harbored the three amino acid substitutions Ile8Phe, Ala146Val, and Lys234Arg. SHV-72 had high catalytic efficiency against penicillins ( k cat / K m , 35 to 287 μM −1 ·s −1 ) and no activity against oxyimino β-lactams. The concentration of clavulanic acid necessary to inhibit the enzyme activity by 50% was 10-fold higher for SHV-72 than for SHV-1. Molecular-dynamics simulation suggested that the Lys234Arg substitution in SHV-72 stabilized an atypical conformation of the Ser130 side chain, which moved the Oγ atom of Ser130 around 3.5 A away from the key Oγ atom of the reactive serine (Ser70). This movement may therefore decrease the susceptibility to clavulanic acid by preventing cross-linking between Ser130 and Ser70.

The Lys234Arg Substitution in the Enzyme SHV-72 Is a Determinant for Resistance to Clavulanic Acid Inhibition

In CTX-M-9 extended-spectrum β-lactamases (ESBLs), an S130G mutation induced a 40- to 650-fold increase in 50% inhibitory concentrations but decreased hydrolytic activity against cefotaxime. A D240K mutation did not modify enzymatic efficiency against ceftazidime. Residue K240 could interact with Q270 and therefore not with ceftazidime, in contrast with what was observed with certain TEM/SHV-type ESBLs.

Effects of Ser130Gly and Asp240Lys Substitutions in Extended-Spectrum β-Lactamase CTX-M-9

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Effects of Ser130Gly and Asp240Lys Substitutions in Extended-Spectrum β-Lactamase CTX-M-9