Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC β-Lactamases in Pseudomonas aeruginosa

Barceló, Isabel; Jordana‐Lluch, Elena; Escobar‐Salom, María; Torrens, Gabriel; Fraile-Ribot, Pablo A; Cabot, Gabriel; Mulet, Xavier; Zamorano, Laura; Juan, Carlos

doi:10.1128/spectrum.02700-22

Cited by 9 publications

(36 citation statements)

References 67 publications

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“…Therefore, based on previous publications ( 56 – 60 ) and our results, we believe that the mildly reduced virulence of Kp52.145RΔAG TC (DHA-1) and Kp52.145RΔAG pUCP-DHA-1 transformant could lean on a greater parallel peptidoglycanase activity of DHA-1 compared to that of CMY-2, which seems devoid of significant associated burdens even when overproduced ( Fig. 1 and 2 ).…”

Section: Resultssupporting

confidence: 75%

“…This circumstance was somehow to be expected, given the wide dissemination of these two enzymes in Enterobacteriaceae, presumably not happening if CMY-2 or DHA-1 production entailed a high biological burden ( 24 – 27 ). Thus, this lack of significant attenuation associated with CMY-2 or DHA-1 is in-line with other transferable β-lactamases of wide distribution, shown to cause no significant fitness costs ( 56 , 57 , 61 – 63 ).…”

Section: Resultssupporting

confidence: 71%

“…On the other hand, it has been reported that peptidoglycan recycling-altered strains pose an ideal background to visualize potentially hidden costs linked to the production of β-lactamases ( 13 , 56 , 57 ), and this is what happened for the expression of bla DHA-1 in Kp52.145RΔAG transconjugant (log-rank test P values <0.05 in all the pairwise comparisons, Fig. 2A ).…”

Section: Resultsmentioning

confidence: 91%

“…In this regard, some studies have shown that the production of certain β-lactamases (e.g., some OXA-2-derived extended spectrum variants) entails dramatic biological costs and virulence attenuations in P. aeruginosa, while similar outputs have been obtained for other gram-negatives. These effects have been proposed to be likely mediated by residual activities of β-lactamases on peptidoglycan and/or muropeptide-based regulatory networks ( 40 , 56 – 60 ). In this study, we wanted to decipher whether or not the production of acquired AmpCs could impair K. pneumoniae pathogenic power in a similar way.…”

Section: Resultsmentioning

confidence: 99%

“…1 and 2 ). In fact, the existence of a residual peptidoglycan-degrading power reminiscent of an alleged PBP ascendance for certain β-lactamases has been proposed, mostly in terms of peptidase activity ( 56 – 60 ). Accordingly, DHA-1 residual activity would then entail a measurable attenuation in bacterial virulence but only in the situation of energy/metabolic alteration linked to peptidoglycan recycling blockade, which would unmask the mild negative effects linked to this β-lactamase.…”

Section: Resultsmentioning

confidence: 99%

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Transferable AmpCs in Klebsiella pneumoniae : interplay with peptidoglycan recycling, mechanisms of hyperproduction, and virulence implications

Barceló,

Escobar-Salom,

Cabot

et al. 2024

Antimicrob Agents Chemother

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Chromosomal and transferable AmpC β-lactamases represent top resistance mechanisms in different gram-negatives, but knowledge regarding the latter, mostly concerning regulation and virulence-related implications, is far from being complete. To fill this gap, we used Klebsiella pneumoniae (KP) and two different plasmid-encoded AmpCs [DHA-1 (AmpR regulator linked, inducible) and CMY-2 (constitutive)] as models to perform a study in which we show that blockade of peptidoglycan recycling through AmpG permease inactivation abolished DHA-1 inducibility but did not affect CMY-2 production and neither did it alter KP pathogenic behavior. Moreover, whereas regular production of both AmpC-type enzymes did not attenuate KP virulence, when bla DHA-1 was expressed in an ampG -defective mutant, Galleria mellonella killing was significantly (but not drastically) attenuated. Spontaneous DHA-1 hyperproducer mutants were readily obtained in vitro , showing slight or insignificant virulence attenuations together with high-level resistance to β-lactams only mildly affected by basal production (e.g., ceftazidime, ceftolozane/tazobactam). By analyzing diverse DHA-1-harboring clinical KP strains, we demonstrate that the natural selection of these hyperproducers is not exceptional (>10% of the collection), whereas mutational inactivation of the typical AmpC hyperproduction-related gene mpl was the most frequent underlying mechanism. The potential silent dissemination of this kind of strains, for which an important fitness cost-related contention barrier does not seem to exist, is envisaged as a neglected threat for most β-lactams effectiveness, including recently introduced combinations. Analyzing whether this phenomenon is applicable to other transferable β-lactamases and species as well as determining the levels of conferred resistance poses an essential topic to be addressed. IMPORTANCE Although there is solid knowledge about the regulation of transferable and especially chromosomal AmpC β-lactamases in Enterobacterales, there are still gaps to fill, mainly related to regulatory mechanisms and virulence interplays of the former. This work addresses them using Klebsiella pneumoniae as model, delving into a barely explored conception: the acquisition of a plasmid-encoded inducible AmpC-type enzyme whose production can be increased through selection of chromosomal mutations, entailing dramatically increased resistance compared to basal expression but minor associated virulence costs. Accordingly, we demonstrate that clinical K. pneumoniae DHA-1 hyperproducer strains are not exceptional. Through this study, we warn for the first time that this phenomenon may be a neglected new threat for β-lactams effectiveness (including some recently introduced ones) silently spreading in the clinical context, not only in K. pneumoniae but potentially also in other pathogens. These facts must be carefully considered in order to design future resistance-preventive strategies.

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Section: Resultssupporting

confidence: 75%

Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Transferable AmpCs in Klebsiella pneumoniae : interplay with peptidoglycan recycling, mechanisms of hyperproduction, and virulence implications

Barceló,

Escobar-Salom,

Cabot

et al. 2024

Antimicrob Agents Chemother

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A Bibliometric Analysis: Current Perspectives and Potential Trends of Enzyme Thermostability from 1991–2022

Zhang

Wang

et al. 2023

Appl Biochem Biotechnol

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Impact of multidrug resistance on the virulence and fitness of Pseudomonas aeruginosa: a microbiological and clinical perspective

Sendra,

Fernández-Muñoz,

Zamorano

et al. 2024

Infection

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Pseudomonas aeruginosa is one of the most common nosocomial pathogens and part of the top emergent species associated with antimicrobial resistance that has become one of the greatest threat to public health in the twenty-first century. This bacterium is provided with a wide set of virulence factors that contribute to pathogenesis in acute and chronic infections. This review aims to summarize the impact of multidrug resistance on the virulence and fitness of P. aeruginosa. Although it is generally assumed that acquisition of resistant determinants is associated with a fitness cost, several studies support that resistance mutations may not be associated with a decrease in virulence and/or that certain compensatory mutations may allow multidrug resistance strains to recover their initial fitness. We discuss the interplay between resistance profiles and virulence from a microbiological perspective but also the clinical consequences in outcomes and the economic impact.

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Role of Enzymatic Activity in the Biological Cost Associated with the Production of AmpC β-Lactamases in Pseudomonas aeruginosa

Cited by 9 publications

References 67 publications

Transferable AmpCs in Klebsiella pneumoniae : interplay with peptidoglycan recycling, mechanisms of hyperproduction, and virulence implications

Transferable AmpCs in Klebsiella pneumoniae : interplay with peptidoglycan recycling, mechanisms of hyperproduction, and virulence implications

A Bibliometric Analysis: Current Perspectives and Potential Trends of Enzyme Thermostability from 1991–2022

Impact of multidrug resistance on the virulence and fitness of Pseudomonas aeruginosa: a microbiological and clinical perspective

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