The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance

Moon, Thomas M.; D'Andrea, E.D.; Lee, Christoper W.; Soares, Alexei S.; Jakoncic, Jean; Desbonnet, Charlene; Solache, Mónica García; Rice, Lou B.; Page, Rebecca; Peti, Wolfgang

doi:10.1074/jbc.ra118.006052

Cited by 49 publications

(37 citation statements)

References 33 publications

(33 reference statements)

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“…The ␤3 strand also undergoes transitions after acylation by antibiotics in other PBP structures, including Staphylococcus aureus PBP2a (29,30), Enterococcus faecalis PBP4 (31), and the Actinomadura R39 DD-peptidase (32). In some of these, ␤3 appears to twist outwards from the active site when acylated by ␤-lactams rather than inward (30,31). By creating an energetic barrier against acylation, the twisting of ␤3 in S. aureus PBP2a has been suggested to be a mechanism for lowering reactivity with ␤-lactams that contributes to resistance (29).…”

Section: Discussionmentioning

confidence: 99%

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

Singh

Tomberg

Nicholas

et al. 2019

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

Singh

Tomberg

Nicholas

et al. 2019

Journal of Biological Chemistry

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“…Inhibition of the activity of high‐molecular weight PBPs (transpeptidases) results in abrogation of peptidoglycan crosslinking and is thought to ultimately contribute to the bactericidal activity of β‐lactams through loss of cell wall integrity . Additionally, different β‐lactams have differing affinities for the different types of PBP that a given bacteria may possess . Among the most clinically relevant gram‐negative bacteria, such as Escherichia coli and P. aeruginosa , imipenem generally exhibits the highest affinity for PBP 2, followed by 1a, 1b, and 3 …”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…[33][34][35] Additionally, different β-lactams have differing affinities for the different types of PBP that a given bacteria may possess. [36][37][38][39] Among the most clinically relevant gram-negative bacteria, such as Escherichia coli and P. aeruginosa, imipenem generally exhibits the highest affinity for PBP 2, followed by 1a, 1b, and 3. 31,40 Relebactam β-Lactamases contribute to antimicrobial resistance by directly inactivating β-lactams through the catalyzing of the hydrolysis of the β-lactam ring, thus reducing the amount of active drug available for inhibition of PBP.…”

Section: Imipenemmentioning

confidence: 99%

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

2020

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Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens.

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“…To determine if low cephalosporin reactivity is an inherent property of PbpA(2b) itself or if the cephalosporin reactivity of PbpA(2b) is modulated by other factors in vivo, we expressed and purified a soluble recombinant E. faecalis PbpA(2b) lacking its N-terminal transmembrane anchor [PbpA(2b) ΔTM]. This strategy has been used previously to investigate structure and function of other enterococcal PBPs (25)(26)(27)(28). Antibiotic competition assays were performed in vitro by incubating the purified protein with various concentrations of antibiotic for 20 min, followed by labeling any remaining unacylated PBP with excess Bocillin FL.…”

Section: Figmentioning

confidence: 99%

Multiple Low-Reactivity Class B Penicillin-Binding Proteins Are Required for Cephalosporin Resistance in Enterococci

Djorić

Little

Kristich

2020

Antimicrob Agents Chemother

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Enterococcus faecalis and Enterococcus faecium are commensals of the gastrointestinal tract of most terrestrial organisms, including humans, and are major causes of health care-associated infections. Such infections are difficult or impossible to treat, as the enterococcal strains responsible are often resistant to multiple antibiotics. One intrinsic resistance trait that is conserved among E. faecalis and E. faecium is cephalosporin resistance, and prior exposure to cephalosporins is one of the most well-known risk factors for acquisition of an enterococcal infection. Cephalosporins inhibit peptidoglycan biosynthesis by acylating the active-site serine of penicillin-binding proteins (PBPs) to prevent the PBPs from catalyzing cross-linking during peptidoglycan synthesis. For decades, a specific PBP (known as Pbp4 or Pbp5) that exhibits low reactivity toward cephalosporins has been thought to be the primary PBP required for cephalosporin resistance. We analyzed other PBPs and report that in both E. faecalis and E. faecium, a second PBP, PbpA(2b), is also required for resistance; notably, the cephalosporin ceftriaxone exhibits a lethal effect on the ΔpbpA mutant. Strikingly, PbpA(2b) exhibits low intrinsic reactivity with cephalosporins in vivo and in vitro. Unlike the Δpbp5 mutant, the ΔpbpA mutant exhibits a variety of phenotypic defects in growth kinetics, cell wall integrity, and cellular morphology, indicating that PbpA(2b) and Pbp5(4) are not functionally redundant and that PbpA(2b) plays a more central role in peptidoglycan synthesis. Collectively, our results shift the current understanding of enterococcal cephalosporin resistance and suggest a model in which PbpA(2b) and Pbp5(4) cooperate to coordinately mediate peptidoglycan cross-linking in the presence of cephalosporins.

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The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into β-lactam resistance

Cited by 49 publications

References 33 publications

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

Multiple Low-Reactivity Class B Penicillin-Binding Proteins Are Required for Cephalosporin Resistance in Enterococci

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