Specific Labeling of Peptidoglycan Precursors as a Tool for Bacterial Cell Wall Studies

Dam, Vincent van; Olrichs, Nick K.; Breukink, Eefjan

doi:10.1002/cbic.200800678

Cited by 29 publications

(24 citation statements)

References 100 publications

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“…A key factor of the efficacy of carbapenems is their ability to bind to multiple different PBPs (81). Since cell wall formation is a dynamic "three-dimensional process" with formation and autolysis occurring at the same time, when PBPs are inhibited, autolysis continues (237). Eventually the peptidoglycan weakens, and the cell bursts due to osmotic pressure.…”

Section: In the Beginning…mentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,115

962

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In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as "slow substrates" or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.Carbapenems play a critically important role in our antibiotic armamentarium. Of the many hundreds of different ␤-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. As a result, they are often used as "last-line agents" or "antibiotics of last resort" when patients with infections become gravely ill or are suspected of harboring resistant bacteria (23,(174)(175)(176)229). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs (189). Several recent studies clearly show that resistance to carbapenems is increasing throughout the world (35,64,73,123,151,155,173,200). Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to ␤-lactamase inhibition. In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.

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Section: In the Beginning…mentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,115

962

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“…The development of novel PG acting agents has lagged; however, because our overall knowledge of PG biosynthesis and turnover is still very limited 2,3 . This is due, in part, to the lack of tools or methods to enable real-time spatiotemporal tracking of PG biosynthesis in live bacterial cells 4,5 . Recently, we have shown that fluorescently modified D-amino acids enable rapid and covalent detection of cell wall biosynthesis, in real time, in live cells, and in a broad range of bacterial species 6 .…”

Section: Introductionmentioning

confidence: 99%

“…The development of tools and methods to enable real-time tracking of the progression of cell wall biosynthesis and peptidoglycan recycling is a problem of significant current interest for which there was no general solution 4,5 . Methods relying on fluorescently-labeled antibiotics such as vancomycin, with high affinity for nascent PG, have had a profound impact on the field, but these methods also have some inherent limitations 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of fluorescent D-amino acids and their use for probing peptidoglycan synthesis and bacterial growth in situ

et al. 2014

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Fluorescent D-amino acids (FDAAs) are efficiently incorporated into the peptidoglycan of diverse bacterial species at the sites of active peptidoglycan biosynthesis, allowing specific and covalent probing of bacterial growth with minimal perturbation. Here, we provide a protocol for the synthesis of four FDAAs emitting light in blue, green or red and for their use in peptidoglycan labeling of live bacteria. Our modular synthesis protocol gives easy access to a library of different FDAAs made with commercially available fluorophores. FDAAs can be synthesized in a typical chemistry laboratory in 2–3 days. The simple labeling procedure involves addition of the FDAAs to the bacterial sample for the desired labeling duration and stopping further label incorporation by fixation or by washing away excess dye. We discuss several scenarios for the use of these labels including short or long labeling durations, and the combination of different labels in pure culture or complex environmental samples. Depending on the experiment, FDAA labeling can take as little as 30 s for a rapidly growing species such as Escherichia coli.

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“…Lipid II carries the basic PG monomer composed of GlcNAc and MurNAc-pentapeptide. Next, lipid II is flipped across the membrane, the PG monomer is cleaved of the undecaprenyl phosphate and incorporated into the growing chain [2]–[4].…”

Section: Introductionmentioning

confidence: 99%

The Metabolic Enzyme ManA Reveals a Link between Cell Wall Integrity and Chromosome Morphology

Elbaz

Ben-Yehuda

2010

PLoS Genet

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Synchronizing cell growth, division and DNA replication is an essential property of all living cells. Accurate coordination of these cellular events is especially crucial for bacteria, which can grow rapidly and undergo multifork replication. Here we show that the metabolic protein ManA, which is a component of mannose phosphotransferase system, participates in cell wall construction of the rod shaped bacterium Bacillus subtilis. When growing rapidly, cells lacking ManA exhibit aberrant cell wall architecture, polyploidy and abnormal chromosome morphologies. We demonstrate that these cellular defects are derived from the role played by ManA in cell wall formation. Furthermore, we show that ManA is required for maintaining the proper carbohydrate composition of the cell wall, particularly of teichoic acid constituents. This perturbed cell wall synthesis causes asynchrony between cell wall elongation, division and nucleoid segregation.

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Specific Labeling of Peptidoglycan Precursors as a Tool for Bacterial Cell Wall Studies

Cited by 29 publications

References 100 publications

Carbapenems: Past, Present, and Future

Carbapenems: Past, Present, and Future

Synthesis of fluorescent D-amino acids and their use for probing peptidoglycan synthesis and bacterial growth in situ

The Metabolic Enzyme ManA Reveals a Link between Cell Wall Integrity and Chromosome Morphology

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