An evolutionarily conserved allosteric site modulates beta-lactamase activity

Avcı, Fatma Gizem; Altinisik, Fatma Ece; Vardar‐Ulu, Didem; Ölmez, Elif Özkırımlı; Akbulut, Berna Sarıyar

doi:10.1080/14756366.2016.1201813

Cited by 18 publications

(19 citation statements)

References 58 publications

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“…Although the novel bicyclic-boronate derivatives, including taniborbactam (which is currently undergoing phase III trials), are predicted to be highly effective in the short term, there is no certainty that resistance to these novel active site inhibitors will not emerge after several years in circulation. To work towards addressing such a risk, which history is teaching us to anticipate, this study provides supporting evidence in line with the alternative allosteric approach for inhibition of class A enzymes; a strategy which has already been receiving steady interest in TEM-1 and KPC-2 ( Horn and Shoichet, 2004 ; Meneksedag et al, 2013 ; Bowman et al, 2015 ; Avcı et al, 2016 ; Hart et al, 2016 ; Grigorenko et al, 2017 ; Galdadas et al, 2018 , 2021 ).…”

Section: Introductionsupporting

confidence: 56%

The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases

et al. 2021

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Class A β-lactamases are known for being able to rapidly gain broad spectrum catalytic efficiency against most β-lactamase inhibitor combinations as a result of elusively minor point mutations. The evolution in class A β-lactamases occurs through optimisation of their dynamic phenotypes at different timescales. At long-timescales, certain conformations are more catalytically permissive than others while at the short timescales, fine-grained optimisation of free energy barriers can improve efficiency in ligand processing by the active site. Free energy barriers, which define all coordinated movements, depend on the flexibility of the secondary structural elements. The most highly conserved residues in class A β-lactamases are hydrophobic nodes that stabilize the core. To assess how the stable hydrophobic core is linked to the structural dynamics of the active site, we carried out adaptively sampled molecular dynamics (MD) simulations in four representative class A β-lactamases (KPC-2, SME-1, TEM-1, and SHV-1). Using Markov State Models (MSM) and unsupervised deep learning, we show that the dynamics of the hydrophobic nodes is used as a metastable relay of kinetic information within the core and is coupled with the catalytically permissive conformation of the active site environment. Our results collectively demonstrate that the class A enzymes described here, share several important dynamic similarities and the hydrophobic nodes comprise of an informative set of dynamic variables in representative class A β-lactamases.

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Section: Introductionsupporting

confidence: 56%

The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases

et al. 2021

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“…One such example is the deep mutational scan of TEM1 β-lactamase (Stiffler et al, 2015). There are residues that are distal from the active-site but are highly sensitive to substitutions, suggesting possible allostery (Avci et al, 2016). However, it is difficult to know if such mutational sensitivity is because of functional allostery or because of a decreased level of secreted protein, for example because of increased proteolysis.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Function Determining and Buried Residues Through Analysis of Saturation Mutagenesis Datasets

Bhasin

Varadarajan

2021

Front. Mol. Biosci.

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Mutational scanning can be used to probe effects of large numbers of point mutations on protein function. Positions affected by mutation are primarily at either buried or at exposed residues directly involved in function, hereafter designated as active-site residues. In the absence of prior structural information, it has not been easy to distinguish between these two categories of residues. We curated and analyzed a set of twelve published deep mutational scanning datasets. The analysis revealed differential patterns of mutational sensitivity and substitution preferences at buried and exposed positions. Prediction of buried-sites solely from the mutational sensitivity data was facilitated by incorporating predicted sequence-based accessibility values. For active-site residues we observed mean sensitivity, specificity and accuracy of 61, 90 and 88% respectively. For buried residues the corresponding figures were 59, 90 and 84% while for exposed non active-site residues these were 98, 44 and 82% respectively. We also identified positions which did not follow these general trends and might require further experimental re-validation. This analysis highlights the ability of deep mutational scans to provide important structural and functional insights, even in the absence of three-dimensional structures determined using conventional structure determination techniques, and also discuss some limitations of the methodology.

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“…the anti βlactamase activities against E. coli bacteria, 2 compounds which are A7, and A11 showed strong anti βlactamase activities resembling that of clavulanic acid, although both of them have no antibacterial activities. These compounds having one or more hydrophobic residue in its structure, this is coming true with the docking results which indicate that the selectivity for the β-lactamase enzyme increases as the compounds became more hydrophobic, as the active binding site pocket of the β-lactamase are mostly hydrophobic in nature 22 .…”

Section: Concerningmentioning

confidence: 76%

Design, synthesis, and evaluation the anti-β-lactamase activity of new sulphathiazole-derived monobactam compounds

Mahmood¹,

Al-Iraqi²,

Abachi³

2020

Iraqi J. Pharm.

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Objectives: β-Lactams are the most successful antibiotics for the management of infectious diseases. Unfortunately, the bacterial production of β-lactamase that hydrolyzes the β-lactam ring can inactivate these drugs. The use of β-lactamase inhibitors like (clavulanic acid) in combination with the β-lactams may reduce this inactivation. The prevalent β-lactamase phenotype is the TEM-1 of class A released by Gram-positive and Gram-negative bacteria. Methods: The docking study with TEM-1 β-lactamase lead to synthesize of new 5 monobactam compounds as the acid chloride derivatives reacted with the Schiff bases compound forming the monobactam ring. The final 5 synthesized compounds were characterized using physical and spectroscopic methods and tested biologically by evaluating their MIC values against 4 strains of β-lactamase Gram-positive and Gram-negative bacteria. The results were compared with those acquired from using clavulanic acid as a co-inhibiter with amoxicillin against the tested bacteria. Results: The results revealed that 2 synthesized compounds showed an anti βlactamase effect resemble to that of clavulanic acid. Conclusion:As conclusion; the β-lactamase active pocket prefers hydrophobic substituents, as the synthesized products with these groups appeared to have the highest affinity.

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An evolutionarily conserved allosteric site modulates beta-lactamase activity

Cited by 18 publications

References 58 publications

The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases

The Role of Hydrophobic Nodes in the Dynamics of Class A β-Lactamases

Prediction of Function Determining and Buried Residues Through Analysis of Saturation Mutagenesis Datasets

Design, synthesis, and evaluation the anti-β-lactamase activity of new sulphathiazole-derived monobactam compounds

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