Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins

King, Andrew; King, D.T.; French, Shawn; Brouillette, Éric; Asli, Abdelhamid; Alexander, J. Andrew N.; Vuckovic, M.; Maiti, Samarendra N.; Parr, Thomas; Brown, Eric D.; Malouin, François; Strynadka, N.C.J.; Wright, Gerard D.

doi:10.1021/acschembio.5b00944

Cited by 51 publications

(63 citation statements)

References 23 publications

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“…3). This is in keeping with PBP3 inhibition causing filamentation of P. aeruginosa, as is the case in E. coli (38).…”

Section: Resultssupporting

confidence: 78%

“…The lesser effects on cell growth, morphology, and MICs when PBP2 was deleted in PA14 (this study) than when it was deleted in PAO1 (29) are of significant interest, as this PBP is considered a potential drug target (30,38). The reason for these differences is not clear but suggests that, at least for PBP2, the background strain affects the severity of the phenotypes.…”

Section: Discussionmentioning

confidence: 85%

“…By developing new non-␤-lactam inhibitors of PBPs that circumvent the action of ␤-lactamases, PBPs could be resurrected as clinical targets. Examples of this approach are the development of boronic acids and diazabicyclooctanes as PBP inhibitors (38,49). Diazabicyclooctanes are known to inhibit E. coli PBP2 and exhibit antimicrobial activity against P. aeruginosa (strain PAO1) (38).…”

Section: Discussionmentioning

confidence: 99%

“…Examples of this approach are the development of boronic acids and diazabicyclooctanes as PBP inhibitors (38,49). Diazabicyclooctanes are known to inhibit E. coli PBP2 and exhibit antimicrobial activity against P. aeruginosa (strain PAO1) (38). They also increase the antimicrobial potency of ␤-lactams, including ceftazidime (50).…”

Section: Discussionmentioning

confidence: 99%

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Penicillin-Binding Protein 3 Is Essential for Growth of Pseudomonas aeruginosa

Chen

Zhang

Davies

2017

Antimicrob Agents Chemother

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Penicillin-binding proteins (PBPs) function as transpeptidases, carboxypeptidases, or endopeptidases during peptidoglycan synthesis in bacteria. As the well-known drug targets for ␤-lactam antibiotics, the physiological functions of PBPs and whether they are essential for growth are of significant interest. The pathogen Pseudomonas aeruginosa poses a particular risk to immunocompromised and cystic fibrosis patients, and infections caused by this pathogen are difficult to treat due to antibiotic resistance. To identify potential drug targets among the PBPs in P. aeruginosa, we performed gene knockouts of all the high-molecular-mass (HMM) PBPs and determined the impacts on cell growth and morphology, susceptibility to ␤-lactams, peptidoglycan structure, virulence, and pathogenicity. Disruptions of the transpeptidase domains of most HMM PBPs, including double disruptions, had only minimal effects on cell growth. The exception was PBP3, where cell growth occurred only when the protein was conditionally expressed on an integrated plasmid. Conditional deletion of PBP3 also caused a defect in cell division and increased susceptibility to ␤-lactams. Knockout of PBP1a led to impaired motility, and this observation, together with its localization at the cell poles, suggests its involvement in flagellar function. Overall, these findings reveal that PBP3 represents the most promising target for drug discovery against P. aeruginosa, whereas other HMM PBPs have less potential.

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“…3). This is in keeping with PBP3 inhibition causing filamentation of P. aeruginosa, as is the case in E. coli (38).…”

Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Penicillin-Binding Protein 3 Is Essential for Growth of Pseudomonas aeruginosa

Chen

Zhang

Davies

2017

Antimicrob Agents Chemother

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“…Binding to PBPs results in spheroplast formation followed by rapid lysis. Furthermore, AVI and developmental DBO inhibitors can also bind to certain PBPs (11)(12)(13). ATM is relatively PBP 3 specific.…”

Section: Clinical Commentarymentioning

confidence: 99%

Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Marshall

Hujer

Rojas

et al. 2017

Antimicrob Agents Chemother

250

155

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Based upon knowledge of the hydrolytic profile of major ␤-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-␤-lactamases (MBLs). Disk diffusion and agarbased antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included bla IMP , bla NDM , bla , bla CTX-M , bla AmpC , and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was Ն21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a Ն4-log 10 -CFU decrease for all groups that had CAZ-AVI with ATM (8 g/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log 10 -CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

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Medicinal Chemistry of β‐Lactam Antibiotics

Testero

Llarrull

Fisher

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The β‐lactam class of antibacterials is a cornerstone of human health. For nearly eight decades, their unparalleled clinical efficacy and clinical safety have made the β‐lactam class preeminent in the treatment of bacterial infection. The relatively brief period in human history during which the β‐lactams have exerted this benefit is a period characterized by continuous medicinal chemistry innovation, seen visibly in the progression from the penicillins to the complex ensemble of β‐lactams (now including also cephalosporins, monobactams, and carbapenems) used in the clinic. The key force behind this innovation is the progressive evolution by bacteria of resistance mechanisms. Today, highly resistant bacteria challenge the way medicinal chemists contemplate the creative alteration of β‐lactam structures, the way the pharmaceutical industry develops β‐lactams (and other antibacterial) structures, and the way the medical community uses antibacterials. This article gives a concise summary of the history of the β‐lactams. Its emphasis is recent structural innovation with respect to the β‐lactams, and with respect to structurally related classes that act to preserve the clinical activity of the β‐lactams through inhibition of bacterial β‐lactam‐hydrolyzing, and thus β‐lactam‐deactivating, enzymes. We integrate these chemistry advances with new biological discoveries with respect to the bactericidal mechanism of the β‐lactams and with respect to bacterial resistance mechanisms. The combination of these perspectives is a foundational perspective to guide the medicinal chemistry future of the β‐lactams.

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Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins

Cited by 51 publications

References 23 publications

Penicillin-Binding Protein 3 Is Essential for Growth of Pseudomonas aeruginosa

Penicillin-Binding Protein 3 Is Essential for Growth of Pseudomonas aeruginosa

Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Medicinal Chemistry of β‐Lactam Antibiotics

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