Penicillin-Binding Protein Occupancy Dataset for 18 β-Lactams and 4 β-Lactamase Inhibitors in Neisseria gonorrhoeae

López-Argüello, Silvia; Montaner, María; Mármol-Salvador, Amanda; Velázquez-Escudero, Ana; Docobo-Pérez, Fernando; Oliver, Antonio; Moyá, Bartolomé

doi:10.1128/spectrum.00692-23

Cited by 3 publications

(1 citation statement)

References 58 publications

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“…The advancement of artificial intelligence has enabled the combination of a medium-throughput image-based assay with machine learning to automatically analyze the activity and polyspecificity of β-lactams against E. coli cells [175]. Related PBP-occupancy experiments have been carried out for various β-lactams in other bacteria [176,177]. Novel assays have also been developed to simultaneously measure the outer membrane permeability of various β-lactams against carbapenem-resistant K. pneumoniae, Enterobacter cloacae, E. coli, and P. aeruginosa [178][179][180][181], which offers important insights into the interactions between β-lactams and PBPs in situ.…”

Section: Understanding the Transpeptidase Targetsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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Section: Understanding the Transpeptidase Targetsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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Recent advances in nanoantibiotics against multidrug-resistant bacteria

Li,

Liu,

Gong

et al. 2023

Nanoscale Adv.

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Molecular Basis of Influence of A501X Mutations in Penicillin-Binding Protein 2 of Neisseria gonorrhoeae Strain 35/02 on Ceftriaxone Resistance

Krivitskaya,

Kuryshkina,

Eremina

et al. 2024

IJMS

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The increase in the resistance of mutant strains of Neisseria gonorrhoeae to the antibiotic ceftriaxone is pronounced in the decrease in the second-order acylation rate constant, k2/KS, by penicillin-binding protein 2 (PBP2). These changes can be caused by both the decrease in the acylation rate constant, k2, and the weakening of the binding affinity, i.e., an increase in the substrate constant, KS. A501X mutations in PBP2 affect second-order acylation rate constants. The PBP2A501V variant exhibits a higher k2/KS value, whereas for PBP2A501R and PBP2A501P variants, these values are lower. We performed molecular dynamic simulations with both classical and QM/MM potentials to model both acylation energy profiles and conformational dynamics of four PBP2 variants to explain the origin of k2/KS changes. The acylation reaction occurs in two elementary steps, specifically, a nucleophilic attack by the oxygen atom of the Ser310 residue and C–N bond cleavage in the β-lactam ring accompanied by the elimination of the leaving group of ceftriaxone. The energy barrier of the first step increases for PBP2 variants with a decrease in the observed k2/KS value. Submicrosecond classic molecular dynamic trajectories with subsequent cluster analysis reveal that the conformation of the β3–β4 loop switches from open to closed and its flexibility decreases for PBP2 variants with a lower k2/KS value. Thus, the experimentally observed decrease in the k2/KS in A501X variants of PBP2 occurs due to both the decrease in the acylation rate constant, k2, and the increase in KS.

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Penicillin-Binding Protein Occupancy Dataset for 18 β-Lactams and 4 β-Lactamase Inhibitors in Neisseria gonorrhoeae

Cited by 3 publications

References 58 publications

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Recent advances in nanoantibiotics against multidrug-resistant bacteria

Molecular Basis of Influence of A501X Mutations in Penicillin-Binding Protein 2 of Neisseria gonorrhoeae Strain 35/02 on Ceftriaxone Resistance

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