<i>Pseudomonas Aeruginosa</i>
            : Targeting Cell-Wall Metabolism for New Antibacterial Discovery and Development

Lamers, Ryan P.; Burrows, Lori L.

doi:10.4155/fmc-2016-0017

Cited by 12 publications

(6 citation statements)

References 144 publications

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“…Therefore, in this worrying conjuncture, new therapeutic solutions are urgently needed if not to kill the microorganism at least to make the infections less harmful for the patient. This would entirely agree with the concept of antivirulence therapies, which are envisaged as excellent and still barely exploited remaining weapons in the described panorama of antibiotic arsenal reduction (14) to be used along with the novel approaches oriented toward the blockade and/or reversion of the pathways leading to ␤-lactam resistance (15,16). Nevertheless, the essential previous step for the development of new therapies is the finding of targets, ergo, weak points to be attacked in the biology of the pathogen.…”

Section: Introductionsupporting

confidence: 63%

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

Juan

Torrens

Barceló

2018

Microbiol Mol Biol Rev

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The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.

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Section: Introductionsupporting

confidence: 63%

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

Juan

Torrens

Barceló

2018

Microbiol Mol Biol Rev

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“…Another practical lesson from this work is that blocking peptidoglycan recycling (e.g., using AmpG inhibitors) might not only be a useful strategy for combating inducible (AmpR-dependent) β-lactam resistance (46, 47) but also AmpR-independent plasmid-mediated AmpCs, frequently seen in members of the family Enterobacteriaceae (48). …”

Section: Discussionmentioning

confidence: 99%

Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?

Pérez-Gallego

Torrens

Castillo-Vera

et al. 2016

mBio

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Understanding the interplay between antibiotic resistance and bacterial fitness and virulence is essential to guide individual treatments and improve global antibiotic policies. A paradigmatic example of a resistance mechanism is the intrinsic inducible chromosomal β-lactamase AmpC from multiple Gram-negative bacteria, including Pseudomonas aeruginosa, a major nosocomial pathogen. The regulation of ampC expression is intimately linked to peptidoglycan recycling, and AmpC-mediated β-lactam resistance is frequently mediated by inactivating mutations in ampD, encoding an N-acetyl-anhydromuramyl-l-alanine amidase, affecting the levels of ampC-activating muropeptides. Here we dissect the impact of the multiple pathways causing AmpC hyperproduction on P. aeruginosa fitness and virulence. Through a detailed analysis, we demonstrate that the lack of all three P. aeruginosa AmpD amidases causes a dramatic effect in fitness and pathogenicity, severely compromising growth rates, motility, and cytotoxicity; the latter effect is likely achieved by repressing key virulence factors, such as protease LasA, phospholipase C, or type III secretion system components. We also show that ampC overexpression is required but not sufficient to confer the growth-motility-cytotoxicity impaired phenotype and that alternative pathways leading to similar levels of ampC hyperexpression and resistance, such as those involving PBP4, had no fitness-virulence cost. Further analysis indicated that fitness-virulence impairment is caused by overexpressing ampC in the absence of cell wall recycling, as reproduced by expressing ampC from a plasmid in an AmpG (muropeptide permease)-deficient background. Thus, our findings represent a major step in the understanding of β-lactam resistance biology and its interplay with fitness and pathogenesis.

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“…Thus, peptidoglycan recycling is envisaged as a candidate target for combating P . aeruginosa resistance [12,13]. …”

Section: Introductionmentioning

confidence: 99%

Targeting the permeability barrier and peptidoglycan recycling pathways to disarm Pseudomonas aeruginosa against the innate immune system

et al. 2017

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Antimicrobial resistance is a continuously increasing threat that severely compromises our antibiotic arsenal and causes thousands of deaths due to hospital-acquired infections by pathogens such as Pseudomonas aeruginosa, situation further aggravated by the limited development of new antibiotics. Thus, alternative strategies such as those targeting bacterial resistance mechanisms, virulence or potentiating the activity of our immune system resources are urgently needed. We have recently shown that mutations simultaneously causing the peptidoglycan recycling blockage and the β-lactamase AmpC overexpression impair the virulence of P.aeruginosa. These findings suggested that peptidoglycan metabolism might be a good target not only for fighting antibiotic resistance, but also for the attenuation of virulence and/or potentiation of our innate immune weapons. Here we analyzed the activity of the innate immune elements peptidoglycan recognition proteins (PGRPs) and lysozyme against P. aeruginosa. We show that while lysozyme and PGRPs have a very modest basal effect over P. aeruginosa, their bactericidal activity is dramatically increased in the presence of subinhibitory concentrations of the permeabilizing agent colistin. We also show that the P. aeruginosa lysozyme inhibitors seem to play a very residual protective role even in permeabilizing conditions. In contrast, we demonstrate that, once the permeability barrier is overpassed, the activity of lysozyme and PGRPs is dramatically enhanced when inhibiting key peptidoglycan recycling components (such as the 3 AmpDs, AmpG or NagZ), indicating a decisive protective role for cell-wall recycling and that direct peptidoglycan-binding supports, at least partially, the activity of these enzymes. Finally, we show that recycling blockade when occurring simultaneously with AmpC overexpression determines a further decrease in the resistance against PGRP2 and lysozyme, linked to quantitative changes in the cell-wall. Thus, our results help to delineate new strategies against P. aeruginosa infections, simultaneously targeting β–lactam resistance, cell-wall metabolism and virulence, ultimately enhancing the activity of our innate immune weapons.

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Pseudomonas Aeruginosa : Targeting Cell-Wall Metabolism for New Antibacterial Discovery and Development

Cited by 12 publications

References 144 publications

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

Interplay between Peptidoglycan Biology and Virulence in Gram-Negative Pathogens

Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?

Targeting the permeability barrier and peptidoglycan recycling pathways to disarm Pseudomonas aeruginosa against the innate immune system

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