Allosteric Inhibition of Bacterial Targets: An Opportunity for Discovery of Novel Antibacterial Classes

Meisel, Jayda E.; Fisher, Jed F.; Chang, Mayland; Mobashery, Shahriar

doi:10.1007/7355_2017_21

Cited by 12 publications

(20 citation statements)

References 176 publications

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“…We hasten to add that such facilitation of catalysis by allostery is likely more common in bacteria (and in nature) than the dearth of examples implied. 31…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

et al. 2018

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Transpeptidases, members of the penicillin-binding protein (PBP) families, catalyze cross-linking of the bacterial cell wall. This transformation is critical for the survival of bacteria, and it is the target of inhibition by β-lactam antibiotics. We report herein our structural insights into catalysis by the essential PBP2x of Streptococcus pneumoniae by disclosing a total of four X-ray structures, two computational models based on the crystal structures, and molecular-dynamics simulations. The X-ray structures are for the apo PBP2x, the enzyme modified covalently in the active site by oxacillin (a penicillin antibiotic), the enzyme modified by oxacillin in the presence of a synthetic tetrasaccharide surrogate for the cell-wall peptidoglycan, and a noncovalent complex of cefepime (a cephalosporin antibiotic) bound to the active site. A prerequisite for catalysis by transpeptidases, including PBP2x, is the molecular recognition of nascent peptidoglycan strands, which harbor pentapeptide stems. We disclose that the recognition of nascent peptidoglycan by PBP2x takes place by complexation of one pentapeptide stem at an allosteric site located in the PASTA domains of this enzyme. This binding predisposes the third pentapeptide stem in the same nascent peptidoglycan strand to penetration into the active site for the turnover events. The complexation of the two pentapeptide stems in the same peptidoglycan strand is a recognition motif for the nascent peptidoglycan, critical for the cell-wall cross-linking reaction.

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“…We hasten to add that such facilitation of catalysis by allostery is likely more common in bacteria (and in nature) than the dearth of examples implied. 31…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

et al. 2018

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“…We discern simple insight and design our next experiment with attention to the singular rather than the plurality of Ockham's razor . The allosteric control of S. aureus PBP2a (and perhaps of other PBPs) may well be to synchronize loop opening of the active site with protein translocation, but this explanation is almost certainly an oversimplification. The narrative presented here conceptualizes a two‐dimensional pathway for the peptidoglycan construction and deconstruction by P. aeruginosa when the realities of both AmpR regulation and cell‐wall biosynthesis are multidimensional .…”

Section: Resultsmentioning

confidence: 99%

“…The active‐site serine is approximately 60 Å distant from the allosteric site. The structural change that occurs in the allosteric transformation that controls substrate access to these active‐site serine is understood by crystallographic evidence, simulations and kinetics data…”

Section: Sensing and Evading The β‐Lactam Antibiotics By A Gram‐positmentioning

confidence: 99%

“…The active-site serine is approximately 60 Å distant from the allosteric site. The structural change that occurs in the allosteric transformation that controls substrate access to these activesite serine is understood by crystallographic evidence, simulations and kinetics data [143][144][145][146] substrate and inactivator. Following translocation, the allosteric site of PBP2a engages existing "template" peptidoglycan so as to trigger the conformational change that opens the active site.…”

Section: Sensing and Evading The β-Lactam Antibiotics By A Gram-posmentioning

confidence: 99%

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Constructing and deconstructing the bacterial cell wall

Fisher

Mobashery

2019

Protein Science

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The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell‐wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre‐eminent class of antibiotics—the β‐lactams, exemplified by the penicillins and cephalosporins—from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the β‐lactams is bacterial cell‐wall destruction. In the monoderm (single membrane, Gram‐positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a β‐lactam‐unreactive transpeptidase enzyme that functions in cell‐wall construction. In the diderm (dual membrane, Gram‐negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical β‐lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell‐wall construction and cell‐wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of β‐lactams. This review summarizes how the β‐lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

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“…PBP2a functions via allosteric regulation of the active binding site for peptidoglycan precursers, which remains “closed” in the presence of traditional β-lactams ( 22 – 24 ). In contrast, newer generation cephalosporins (ceftaroline; ceftabiprole) are able to open such sites ( 25 , 26 ).…”

Section: Introductionmentioning

confidence: 99%

The NaHCO ₃ -Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus (MRSA) Is Influenced by mecA Genotype

Ersoy¹,

Manna

Proctor

et al. 2022

Antimicrob Agents Chemother

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Methicillin-resistant Staphylococcus aureus (MRSA) strains are a leading cause of many invasive clinical syndromes, and pose treatment difficulties due to their in vitro resistance to most β-lactams on standard laboratory testing. A novel phenotype frequently identified in MRSA strains, termed ‘NaHCO 3 -responsiveness’, is a property whereby strains are susceptible in vitro to many β-lactams in the presence of NaHCO 3 .

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Allosteric Inhibition of Bacterial Targets: An Opportunity for Discovery of Novel Antibacterial Classes

Cited by 12 publications

References 176 publications

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

Constructing and deconstructing the bacterial cell wall

The NaHCO ₃ -Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus (MRSA) Is Influenced by mecA Genotype

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Allosteric Inhibition of Bacterial Targets: An Opportunity for Discovery of Novel Antibacterial Classes

Cited by 12 publications

References 176 publications

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

Allostery, Recognition of Nascent Peptidoglycan, and Cross-linking of the Cell Wall by the Essential Penicillin-Binding Protein 2x of Streptococcus pneumoniae

Constructing and deconstructing the bacterial cell wall

The NaHCO 3 -Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus (MRSA) Is Influenced by mecA Genotype

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The NaHCO ₃ -Responsive Phenotype in Methicillin-Resistant Staphylococcus aureus (MRSA) Is Influenced by mecA Genotype