Blocking Peptidoglycan Recycling in <i>Pseudomonas aeruginosa</i> Attenuates Intrinsic Resistance to Fosfomycin

Borisova, Marina; Gisin, Jonathan; Mayer, Christoph

doi:10.1089/mdr.2014.0036

Cited by 69 publications

(79 citation statements)

References 41 publications

(46 reference statements)

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“…Consequently, the fosfomycin target (MurA) is not involved in peptidoglycan synthesis, resulting in inherent fosfomycin resistance. A similar pathway was recently described for Pseudomonas aeruginosa (10).…”

Section: Inherent Resistancementioning

confidence: 63%

“…It inhibits an enzyme-catalyzed reaction in the first step of the synthesis of the bacterial cell wall (9). Fosfomycin interferes with the first cytoplasmic step of bacterial cell wall biosynthesis, the formation of the peptidoglycan precursor UDP N-acetylmuramic acid (UDPMurNAc) (10). Specifically, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is involved in peptidoglycan biosynthesis by catalyzing the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 3=-hydroxyl group of UDP-N-acetylglucosamine (UNAG) (11).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Fosfomycin

et al. 2016

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SUMMARYThe treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, thein vitroactivity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed.

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Section: Inherent Resistancementioning

confidence: 63%

Section: Mechanism Of Actionmentioning

confidence: 99%

Fosfomycin

et al. 2016

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“…Homologues of NagA (PA3758), GlmM (PA4749) and GlmS (PA5549) are found in P. aeruginosa. This novel alternative pathway was identified in P. aeruginosa and P. putida [174,178]. Homologues of AmgK and MurU have been identified in Proteobacteria but not in Enterobacteria [174].…”

Section: Convergence Of Recycling and Biosynthesismentioning

confidence: 97%

“…In P. aeruginosa, an AnmK homologue PA0666 phosphorylates anhMurNAc to form MurNAc-6-P; subsequently, the phosphate is removed by MupP (PA3172) resulting in MurNAc [174][175][176][177]. MurNAc is further processed by two enzymes AmgK (PA0596) and MurU (PA0597) unique to pseudomonads encoded in the same operon [178].…”

Section: Convergence Of Recycling and Biosynthesismentioning

confidence: 99%

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Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Dhar

Kumari

Balasubramanian

et al. 2018

Journal of Medical Microbiology

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The bacterial cell-wall that forms a protective layer over the inner membrane is called the murein sacculus -a tightly crosslinked peptidoglycan mesh unique to bacteria. Cell-wall synthesis and recycling are critical cellular processes essential for cell growth, elongation and division. Both de novo synthesis and recycling involve an array of enzymes across all cellular compartments, namely the outer membrane, periplasm, inner membrane and cytoplasm. Due to the exclusivity of peptidoglycan in the bacterial cell-wall, these players are the target of choice for many antibacterial agents. Our current understanding of cell-wall biochemistry and biogenesis in Gram-negative organisms stems mostly from studies of Escherichia coli. An incomplete knowledge on these processes exists for the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa. In this review, cell-wall synthesis and recycling in the various cellular compartments are compared and contrasted between E. coli and P. aeruginosa. Despite the fact that there is a remarkable similarity of these processes between the two bacterial species, crucial differences alter their resistance to b-lactams, fluoroquinolones and aminoglycosides. One of the common mediators underlying resistance is the amp system whose mechanism of action is closely associated with the cell-wall recycling pathway. The activation of amp genes results in expression of AmpC blactamase through its cognate regulator AmpR which further regulates multi-drug resistance. In addition, other cell-wall recycling enzymes also contribute to antibiotic resistance. This comprehensive summary of the information should spawn new ideas on how to effectively target cell-wall processes to combat the growing resistance to existing antibiotics.

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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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Blocking Peptidoglycan Recycling in Pseudomonas aeruginosa Attenuates Intrinsic Resistance to Fosfomycin

Cited by 69 publications

References 41 publications

Fosfomycin

Fosfomycin

Cell-wall recycling and synthesis in Escherichia coli and Pseudomonas aeruginosa – their role in the development of resistance

Medicinal Chemistry of β‐Lactam Antibiotics

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