Systematic substitutions at BLIP position 50 result in changes in binding specificity for class A β-lactamases

Adamski, Carolyn J.; Palzkill, Timothy

doi:10.1186/s12858-017-0077-1

Cited by 5 publications

(6 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Note that even the tightest and weakest substitutions differ among the datasets. Data were taken from Adamski and Palzkill (2017) LPYK and LacI show coincidence between the locations of their multi-rheostat positions and regions of the protein involved in allosteric coupling, suggesting that multi-rheostat positions are enriched in and near allosteric sites. Given the uncorrelation and (as of yet) unpredictable outcomes on multiple functional parameters, these types of rheostat positions could be one thing that confounds predictions about substitutions of rheostat positions.…”

Section: Rheostatic Outcomes Affect Various Aspects Of Protein Functionmentioning

confidence: 96%

“…4; (Procko 2020)), and the β-lactamase inhibitory protein ("BLIP"; Fig. 5; (Adamski and Palzkill 2017)).…”

Section: Rheostatic Outcomes Affect Various Aspects Of Protein Functionmentioning

confidence: 99%

“…However, the rank order of the variant proteins was dependent on which of the three betalactamases was used as the binding partner ( Fig. 5; (Adamski and Palzkill 2017)). This change in rank order provides another means to assess altered specificity.…”

Section: Rheostatic Outcomes Affect Various Aspects Of Protein Functionmentioning

confidence: 99%

See 2 more Smart Citations

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

et al. 2020

View full text Add to dashboard Cite

To achieve the full potential of pharmacogenomics, one must accurately predict the functional outcomes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as "toggle" switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches ("rheostat" positions): this is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans a range of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This paper reviews the currently-known properties of rheostat positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework-comprising three types of protein positions-provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution outcomes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.

show abstract

Section: Rheostatic Outcomes Affect Various Aspects Of Protein Functionmentioning

confidence: 96%

“…4; (Procko 2020)), and the β-lactamase inhibitory protein ("BLIP"; Fig. 5; (Adamski and Palzkill 2017)).…”

Section: Rheostatic Outcomes Affect Various Aspects Of Protein Functionmentioning

confidence: 99%

See 1 more Smart Citation

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Alternatively, “narrow spectrum” inhibitors should not be discounted for therapeutic purposes as they will likely cause less damage to the patients beneficial microbiome (Boucher et al, 2017 ). Another approach is to utilize naturally observed protein inhibitors of β-lactamases from Streptomyces , termed β-lactamase inhibitor proteins (BLIPs), which can be altered to modulate β-lactamase specificity (Brown et al, 2013 ; Chow et al, 2016 ; Adamski and Palzkill, 2017a , b ); peptides derived from BLIPs have been shown to have antimicrobial activity (Alaybeyoglu et al, 2015 ).…”

Section: Additional Inhibitor Design Approachesmentioning

confidence: 99%

Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

Akker

Bonomo

2018

Front. Microbiol.

View full text Add to dashboard Cite

As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase. Most of these compounds are “mechanism-based” inhibitors that in some manner mimic the β-lactam substrate, having a carbonyl moiety and a negatively charged carboxyl or sulfate group. These compounds form a covalent adduct with the catalytic serine via an initial acylation step. To increase the life-time of the inhibitory covalent adduct intermediates, a remarkable array of different strategies was employed to improve inhibition potency. Such approaches include post-acylation intra- and intermolecular chemical rearrangements as well as affecting the deacylation water. These approaches transform the inhibitor design process from a 3-dimensional problem (i.e., XYZ coordinates) to one with additional dimensions of complexity as the reaction coordinate and time spent at each chemical state need to be taken into consideration. This review highlights the mechanistic intricacies of the design efforts of the β-lactamase inhibitors which so far have resulted in the development of “two generations” and 5 clinically available inhibitors.

show abstract

“…However, these polar residues are still abundantly found on the binding interface, thus suggesting a role that is still unclear. This point has been reiterated in a recent publication in which Adamski and Palzkill [ 93 ] examined the effects of different amino acid (i.e., non-polar, small and polar residues) substitutions on the binding affinity of Tyr50.…”

Section: -Lactamase Inhibitor Proteinsmentioning

confidence: 97%

Tackling the Antibiotic Resistance Caused by Class A β-Lactamases through the Use of β-Lactamase Inhibitory Protein

Eiamphungporn

Schaduangrat

Malik

et al. 2018

IJMS

View full text Add to dashboard Cite

β-Lactams are the most widely used and effective antibiotics for the treatment of infectious diseases. Unfortunately, bacteria have developed several mechanisms to combat these therapeutic agents. One of the major resistance mechanisms involves the production of β-lactamase that hydrolyzes the β-lactam ring thereby inactivating the drug. To overcome this threat, the small molecule β-lactamase inhibitors (e.g., clavulanic acid, sulbactam and tazobactam) have been used in combination with β-lactams for treatment. However, the bacterial resistance to this kind of combination therapy has evolved recently. Therefore, multiple attempts have been made to discover and develop novel broad-spectrum β-lactamase inhibitors that sufficiently work against β-lactamase producing bacteria. β-lactamase inhibitory proteins (BLIPs) (e.g., BLIP, BLIP-I and BLIP-II) are potential inhibitors that have been found from soil bacterium Streptomyces spp. BLIPs bind and inhibit a wide range of class A β-lactamases from a diverse set of Gram-positive and Gram-negative bacteria, including TEM-1, PC1, SME-1, SHV-1 and KPC-2. To the best of our knowledge, this article represents the first systematic review on β-lactamase inhibitors with a particular focus on BLIPs and their inherent properties that favorably position them as a source of biologically-inspired drugs to combat antimicrobial resistance. Furthermore, an extensive compilation of binding data from β-lactamase–BLIP interaction studies is presented herein. Such information help to provide key insights into the origin of interaction that may be useful for rationally guiding future drug design efforts.

show abstract

Systematic substitutions at BLIP position 50 result in changes in binding specificity for class A β-lactamases

Cited by 5 publications

References 41 publications

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches

Tackling the Antibiotic Resistance Caused by Class A β-Lactamases through the Use of β-Lactamase Inhibitory Protein

Contact Info

Product

Resources

About