Development of New Drugs for an Old Target — The Penicillin Binding Proteins

Zervosen, Astrid; Sauvage, Eric; Frère, Jean‐Marie; Charlier, Paulette; Luxen, André

doi:10.3390/molecules171112478

Cited by 94 publications

(70 citation statements)

References 106 publications

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“…Rhodanines inhibit classes A and C SBLs (for example, TEM-1 from Escherichia coli, P99 from Enterobacter cloacae and AmpC from Serratia marcescens/Pseudomonas aeruginosa 12 ), and some rhodanines also have antimicrobial activity due to non-competitive or competitive PBP inhibition (PBP2x from Staphylococcus aureus or Neisseria gonorrhoea; for details see Supplementary Fig. 1) 13,14 . We were therefore interested in a recent report of a potent and broadly active rhodanine-based MBL inhibitor, ML302 15 .…”

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Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

et al. 2014

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The use of β-lactam antibiotics is compromised by resistance, which is provided by β-lactamases belonging to both metallo (MBL)- and serine (SBL)-β-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in β-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including (19)F NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.

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Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

et al. 2014

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“…␤-Lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) have been the mainstay of treatment for Gramnegative bacterial infections since the discovery of penicillin in the 1940s (4,5). Resistance to ␤-lactams poses a significant threat to the continued successful treatment of both common and opportunistic pathogens (6).…”

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“…Resistance to ␤-lactams poses a significant threat to the continued successful treatment of both common and opportunistic pathogens (6). Resistant pathogens evolve a variety of features, including changes in the drug targets (the penicillin-binding proteins of the bacterial cell wall), impaired permeability (including increased mucosity, the absence of porins, and/or the presence of efflux pumps), and the presence of enzymes with the ability to inactivate the antibiotics (i.e., ␤-lactamase enzymes) (5,6). Importantly, ␤-lactamase enzymes are evolving to confer resistance to all classes of ␤-lactam antibiotics (e.g., KPC-2, CTX-M-15, OXA, and AmpC enzymes) (5).…”

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“…Resistant pathogens evolve a variety of features, including changes in the drug targets (the penicillin-binding proteins of the bacterial cell wall), impaired permeability (including increased mucosity, the absence of porins, and/or the presence of efflux pumps), and the presence of enzymes with the ability to inactivate the antibiotics (i.e., ␤-lactamase enzymes) (5,6). Importantly, ␤-lactamase enzymes are evolving to confer resistance to all classes of ␤-lactam antibiotics (e.g., KPC-2, CTX-M-15, OXA, and AmpC enzymes) (5). An approach to combat infections by bacteria containing such enzymes is the development of ␤-lactamase inhibitors (BLIs), which act to cripple the catalytic capacity of the enzyme (Fig.…”

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Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa

Winkler

Papp-Wallace

Hujer

et al. 2015

Antimicrob Agents Chemother

124

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e Pseudomonas aeruginosa is a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of ␤-lactam-resistant P. aeruginosa clinical isolates from a decade ago, we uncovered resistance to ceftazidimeavibactam, a novel ␤-lactam/␤-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC ␤-lactamase enzymes and that bla PDC regulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) targeting multiple cell wall synthetic pathways can restore susceptibility. In P. aeruginosa, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the development of antimicrobial agents targeted for the treatment of multidrugresistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors.

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“…seudomonas aeruginosa is an opportunistic pathogen associated with numerous nosocomial infections, where ␤-lactam antibiotics remain key in treatment (1,2). One of the major antimicrobials used to fight P. aeruginosa infections is ceftazidime (CAZ), a well-known cephalosporin that acts primarily as a penicillin-binding protein 3 (PBP3) inhibitor (3,4).…”

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Elucidation of Mechanisms of Ceftazidime Resistance among Clinical Isolates of Pseudomonas aeruginosa by Using Genomic Data

Kos

McLaughlin

Gardner

2016

Antimicrob Agents Chemother

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Ceftazidime is one of the few cephalosporins with activity against Pseudomonas aeruginosa. Using whole-genome comparative analysis, we set out to determine the prevalent mechanism(s) of resistance to ceftazidime (CAZ) using a set of 181 clinical isolates. These isolates represented various multilocus sequence types that consisted of both ceftazidime-susceptible and -resistant populations. A presumptive resistance mechanism against ceftazidime was identified in 88% of the nonsusceptible isolates using this approach. Pseudomonas aeruginosa is an opportunistic pathogen associated with numerous nosocomial infections, where ␤-lactam antibiotics remain key in treatment (1, 2). One of the major antimicrobials used to fight P. aeruginosa infections is ceftazidime (CAZ), a well-known cephalosporin that acts primarily as a penicillin-binding protein 3 (PBP3) inhibitor (3,4).A significant proportion of ceftazidime-resistant isolates arise through the horizontal acquisition of ␤-lactamases or altered expression of the chromosomal drug-inducible wide-spectrum class C ␤-lactamase AmpC (reviewed in reference 5). The overproduction of AmpC can result from mutations affecting the peptidoglycan (PG) recycling process, where accumulation of cell wall intermediates ultimately induces ampC overexpression (5).We focused our study on a panel of 181 clinical P. aeruginosa isolates, where comparative analysis between multiple isolates belonging to the same multilocus sequence types (MLSTs) allowed for identification of chromosomal gene variants unique to the ceftazidime-resistant population (6).The initial MIC to ceftazidime was determined using frozen plates (Thermo Scientific) following the Clinical and Laboratory Standards Institute guidelines (7,8). Of the 181 isolates in the analysis set, 99 (55%) were resistant to ceftazidime (MIC, Ն16 g/ml), and 82 were susceptible (MIC, Յ8 g/ml) ( Table 1; see Table S1 in the supplemental material).Genomic analysis (see Table S1 in the supplemental material) was performed using CLC Genomic Workbench 7.0.4 (CLCBio). Unique sequence variants exclusive to the resistant population of each MLST group were flagged for further analysis as outlined in the summary column of Table S1. To account for resistance in the 99 ceftazidime-resistant isolates in a parsimonious manner, we followed a triage process-accounting first for resistance-inducing ␤-lactamases, second for mechanisms allowing for derepression of ampC, and third for other candidate causes of resistance.Forty-six isolates had ␤-lactamases that have been reported to hydrolyze ceftazidime (Table 1). Analysis of the ampC regulon and additional cephalosporin targets was also completed for these isolates (see Table S1 in the supplemental material); however, resistance was attributed primarily to the presence of the ␤-lactamases, as clinically, detection of such an element would rule out treatment with ceftazidime. It was apparent that certain MLST lineages were enriched in ␤-lactamases, particularly sequence type 111 (ST111) and ST233, which were t...

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Development of New Drugs for an Old Target — The Penicillin Binding Proteins

Cited by 94 publications

References 106 publications

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition

Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa

Elucidation of Mechanisms of Ceftazidime Resistance among Clinical Isolates of Pseudomonas aeruginosa by Using Genomic Data

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