PorinPredict:
            <i>In Silico</i>
            Identification of OprD Loss from WGS Data for Improved Genotype-Phenotype Predictions of P. aeruginosa Carbapenem Resistance

Biggel, Michael; Johler, Sophia; Roloff, Tim; Tschudin‐Sutter, Sarah; Bassetti, Stefano; Siegemund, Martin; Egli, Adrian; Stephan, Roger; Seth-Smith, Helena M. B.

doi:10.1128/spectrum.03588-22

Cited by 8 publications

(4 citation statements)

References 47 publications

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“…[ 52 ]. The functionality of the outer-membrane porin oprD was analyzed in silico using the recently described PorinPredict tool [ 53 ].…”

Section: Methodsmentioning

confidence: 99%

Genomic Characterization of IMP-Producing Pseudomonas aeruginosa in Bulgaria Reveals the Emergence of IMP-100, a Novel Plasmid-Mediated Variant Coexisting with a Chromosomal VIM-4

Stoikov,

Ivanov,

Donchev

et al. 2023

Microorganisms

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Multidrug-resistant (MDR) Pseudomonas aeruginosa infections represent a major public health concern and require comprehensive understanding of their genetic makeup. This study investigated the first occurrence of imipenemase (IMP)-carrying P. aeruginosa strains from Bulgaria. Whole genome sequencing identified a novel plasmid-mediated IMP-100 allele located in a a novel In4886 integron embedded in a putative Tn7700 transposon. Two other closely related chromosomal IMP variants, IMP-13 and IMP-84, were also detected. The IMP-producers were resistant to last-line drugs including cefiderocol (CFDC) (two out of three) and susceptible to colistin. The IMP-13/84 cassettes were situated in a In320 integron inserted in a Tn5051-like transposon as previously reported. Lastly, the p4782-IMP plasmid rendered the PA01 transformant resistant to CFDC, suggesting a transferable CFDC resistance. A variety of virulence factors associated with adhesion, antiphagocytosis, iron uptake, and quorum sensing, as well as secretion systems, toxins, and proteases, were confirmed, suggesting significant pathogenic potential consistent with the observed strong biofilm formation. The emergence of IMP-producing MDR P. aeruginosa is alarming as it remains unsusceptible even to last-generation drugs like CFDC. Newly detected IMP-100 was even located in a CFDC-resistant XDR strain.

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“…[ 52 ]. The functionality of the outer-membrane porin oprD was analyzed in silico using the recently described PorinPredict tool [ 53 ].…”

Section: Methodsmentioning

confidence: 99%

Genomic Characterization of IMP-Producing Pseudomonas aeruginosa in Bulgaria Reveals the Emergence of IMP-100, a Novel Plasmid-Mediated Variant Coexisting with a Chromosomal VIM-4

Stoikov,

Ivanov,

Donchev

et al. 2023

Microorganisms

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“…A number of studies have shown that inactivation of OprD due to mutations inside the open reading frame (ORF) and reduced expression of OprD due to mutations in the promoter or its regulators are frequently observed in clinical P. aeruginosa isolates (Biggel et al., 2023 ; Sherrard et al., 2022 ; Shu et al., 2017 ). Inactivation of OprD contributes significantly to the carbapenem resistance of P. aeruginosa .…”

Section: Porins In P Aeruginosamentioning

confidence: 99%

Antibiotic influx and efflux in Pseudomonas aeruginosa: Regulation and therapeutic implications

Wu,

Huang,

2024

Microbial Biotechnology

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Pseudomonas aeruginosa is a notorious multidrug‐resistant pathogen that poses a serious and growing threat to the worldwide public health. The expression of resistance determinants is exquisitely modulated by the abundant regulatory proteins and the intricate signal sensing and transduction systems in this pathogen. Downregulation of antibiotic influx porin proteins and upregulation of antibiotic efflux pump systems owing to mutational changes in their regulators or the presence of distinct inducing molecular signals represent two of the most efficient mechanisms that restrict intracellular antibiotic accumulation and enable P. aeruginosa to resist multiple antibiotics. Treatment of P. aeruginosa infections is extremely challenging due to the highly inducible mechanism of antibiotic resistance. This review comprehensively summarizes the regulatory networks of the major porin proteins (OprD and OprH) and efflux pumps (MexAB‐OprM, MexCD‐OprJ, MexEF‐OprN, and MexXY) that play critical roles in antibiotic influx and efflux in P. aeruginosa. It also discusses promising therapeutic approaches using safe and efficient adjuvants to enhance the efficacy of conventional antibiotics to combat multidrug‐resistant P. aeruginosa by controlling the expression levels of porins and efflux pumps. This review not only highlights the complexity of the regulatory network that induces antibiotic resistance in P. aeruginosa but also provides important therapeutic implications in targeting the inducible mechanism of resistance.

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“…A potential solution for the latter problem is to move beyond phenotypic (growth-based) susceptibility testing, and to use bacterial whole genome sequences (WGS) to infer antimicrobial susceptibility (38)(39)(40)(41)(42). However, most WGS-based approaches focus on finding known resistance mechanisms and while they are successful in that, identifying (combinations of) mutations in one or more genes not previously associated with reduced susceptibility, and incorporating these in a prediction algorithm, remains a major challenge (43).…”

Section: Genomic Detection Of Resistance Mechanismsmentioning

confidence: 99%

Biofilm antimicrobial susceptibility testing: where are we and where could we be going?

Coenye

2023

Clin Microbiol Rev

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SUMMARY Our knowledge about the fundamental aspects of biofilm biology, including the mechanisms behind the reduced antimicrobial susceptibility of biofilms, has increased drastically over the last decades. However, this knowledge has so far not been translated into major changes in clinical practice. While the biofilm concept is increasingly on the radar of clinical microbiologists, physicians, and healthcare professionals in general, the standardized tools to study biofilms in the clinical microbiology laboratory are still lacking; one area in which this is particularly obvious is that of antimicrobial susceptibility testing (AST). It is generally accepted that the biofilm lifestyle has a tremendous impact on antibiotic susceptibility, yet AST is typically still carried out with planktonic cells. On top of that, the microenvironment at the site of infection is an important driver for microbial physiology and hence susceptibility; but this is poorly reflected in current AST methods. The goal of this review is to provide an overview of the state of the art concerning biofilm AST and highlight the knowledge gaps in this area. Subsequently, potential ways to improve biofilm-based AST will be discussed. Finally, bottlenecks currently preventing the use of biofilm AST in clinical practice, as well as the steps needed to get past these bottlenecks, will be discussed.

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PorinPredict: In Silico Identification of OprD Loss from WGS Data for Improved Genotype-Phenotype Predictions of P. aeruginosa Carbapenem Resistance

Abstract: Pseudomonas aeruginosa is a major cause of multidrug-resistant nosocomial infections. The emergence and spread of clones exhibiting resistance to carbapenems, a class of critical last-line antibiotics, is therefore closely monitored.

Cited by 8 publications

References 47 publications

Genomic Characterization of IMP-Producing Pseudomonas aeruginosa in Bulgaria Reveals the Emergence of IMP-100, a Novel Plasmid-Mediated Variant Coexisting with a Chromosomal VIM-4

Genomic Characterization of IMP-Producing Pseudomonas aeruginosa in Bulgaria Reveals the Emergence of IMP-100, a Novel Plasmid-Mediated Variant Coexisting with a Chromosomal VIM-4

Antibiotic influx and efflux in Pseudomonas aeruginosa: Regulation and therapeutic implications

Biofilm antimicrobial susceptibility testing: where are we and where could we be going?

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