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      Association between possession of ExoU and antibiotic resistance in Pseudomonas aeruginosa

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          Abstract

          Virulent strains of Pseudomonas aeruginosa are often associated with an acquired cytotoxic protein, exoenzyme U (ExoU) that rapidly destroys the cell membranes of host cells by its phospholipase activity. Strains possessing the exoU gene are predominant in eye infections and are more resistant to antibiotics. Thus, it is essential to understand treatment options for these strains. Here, we have investigated the resistance profiles and genes associated with resistance for fluoroquinolone and beta-lactams. A total of 22 strains of P. aeruginosa from anterior eye infections, microbial keratitis (MK), and the lungs of cystic fibrosis (CF) patients were used. Based on whole genome sequencing, the prevalence of the exoU gene was 61.5% in MK isolates whereas none of the CF isolates possessed this gene. Overall, higher antibiotic resistance was observed in the isolates possessing exoU. Of the exoU strains, all except one were resistant to fluoroquinolones, 100% were resistant to beta-lactams. 75% had mutations in quinolone resistance determining regions (T81I gyrA and/or S87L parC) which correlated with fluoroquinolone resistance. In addition, exoU strains had mutations at K76Q, A110T, and V126E in ampC, Q155I and V356I in ampR and E114A, G283E, and M288R in mexR genes that are associated with higher beta-lactamase and efflux pump activities. In contrast, such mutations were not observed in the strains lacking exoU. The expression of the ampC gene increased by up to nine-fold in all eight exoU strains and the ampR was upregulated in seven exoU strains compared to PAO1. The expression of mexR gene was 1.4 to 3.6 fold lower in 75% of exoU strains. This study highlights the association between virulence traits and antibiotic resistance in pathogenic P. aeruginosa.

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          Efflux-mediated antimicrobial resistance.

          Keith Poole (2005)
          Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious disease. And while true biocide resistance is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are common and the history of antibiotic resistance should not be ignored in the development and use of biocidal agents. Efflux mechanisms of resistance, both drug specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials, with some accommodating both antibiotics and biocides. This latter raises the spectre (as yet generally unrealized) of biocide selection of multiple antibiotic-resistant organisms. Multidrug efflux mechanisms are broadly conserved in bacteria, are almost invariably chromosome-encoded and their expression in many instances results from mutations in regulatory genes. In contrast, drug-specific efflux mechanisms are generally encoded by plasmids and/or other mobile genetic elements (transposons, integrons) that carry additional resistance genes, and so their ready acquisition is compounded by their association with multidrug resistance. While there is some support for the latter efflux systems arising from efflux determinants of self-protection in antibiotic-producing Streptomyces spp. and, thus, intended as drug exporters, increasingly, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, appear not to be intended as drug exporters but as exporters with, perhaps, a variety of other roles in bacterial cells. Still, given the clinical significance of multidrug (and drug-specific) exporters, efflux must be considered in formulating strategies/approaches to treating drug-resistant infections, both in the development of new agents, for example, less impacted by efflux and in targeting efflux directly with efflux inhibitors.
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            Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa.

            S. Ohya, H Tsujimoto, N Gotoh … (2000)
            To find the exact substrate specificities of three species of tripartite efflux systems of Pseudomonas aeruginosa, MexAB-OprM, MexCD-OprJ, and MexXY-OprM, we constructed a series of isogenic mutants, each of which constitutively overproduced one of the three efflux systems and lacked the other two, and their isogenic mutants, which lacked all these systems. Comparison of the susceptibilities of the constructed mutants to 52 antimicrobial agents belonging to various groups suggested the following substrate specificities. All of the efflux systems extrude a wide variety of antimicrobial agent groups, i.e., quinolones, macrolides, tetracyclines, lincomycin, chloramphenicol, most penicillins (all but carbenicillin and sulbenicillin), most cephems (all but cefsulodin and ceftazidime), meropenem, and S-4661, but none of them extrude polymyxin B or imipenem. Extrusion of aminoglycosides is specific to MexXY-OprM, and extrusion of a group of the beta-lactams, i.e., carbenicillin, sulbenicillin, ceftazidime, moxalactam, and aztreonam, is specific to MexAB-OprM. Moreover, MexAB-OprM and MexCD-OprJ extrude novobiocin, cefsulodin, and flomoxef, while MexXY-OprM does not. These substrate specificities are distinct from those reported previously.
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              Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System.

              R. Gaynes, Stephen M Richards, Yvonne J K Edwards … (1999)
              To describe the epidemiology of nosocomial infections in medical intensive care units (ICUs) in the United States. Analysis of ICU surveillance data collected through the National Nosocomial Infections Surveillance (NNIS) System between 1992 and 1997. Medical ICUs in the United States. A total of 181,993 patients. Nosocomial infections were analyzed by infection site and pathogen distribution. Urinary tract infections were most frequent (31%), followed by pneumonia (27%) and primary bloodstream infections (19%). Eighty-seven percent of primary bloodstream infections were associated with central lines, 86% of nosocomial pneumonia was associated with mechanical ventilation, and 95% of urinary tract infections were associated with urinary catheters. Coagulase-negative staphylococci (36%) were the most common bloodstream infection isolates, followed by enterococci (16%) and Staphylococcus aureus (13%). Twelve percent of bloodstream isolates were fungi. The most frequent isolates from pneumonia were Gram-negative aerobic organisms (64%). Pseudomonas aeruginosa (21%) was the most frequently isolated of these. S. aureus (20%) was isolated with similar frequency. Candida albicans was the most common single pathogen isolated from urine and made up just over half of the fungal isolates. Fungal urinary infections were associated with asymptomatic funguria rather than symptomatic urinary tract infections (p < .0001). Certain pathogens were associated with device use: coagulase-negative staphylococci with central lines, P. aeruginosa and Acinetobacter species with ventilators, and fungal infections with urinary catheters. Patient nosocomial infection rates for the major sites correlated strongly with device use. Device exposure was controlled for by calculating device-associated infection rates for bloodstream infections, pneumonia, and urinary tract infections by dividing the number of device-associated infections by the number of days of device use. There was no association between these device-associated infection rates and number of hospital beds, number of ICU beds, or length of stay. There is a considerable variation within the distribution of each of these infection rates. The distribution of sites of infection in medical ICUs differed from that previously reported in NNIS ICU surveillance studies, largely as a result of anticipated low rates of surgical site infections. Primary bloodstream infections, pneumonia, and urinary tract infections associated with invasive devices made up the great majority of nosocomial infections. Coagulase-negative staphylococci were more frequently associated with primary bloodstream infections than reported from NNIS ICUs of all types in the 1980s, and enterococci were a more frequent isolate from bloodstream infections than S. aureus. Fungal urinary tract infections, often asymptomatic and associated with catheter use, were considerably more frequent than previously reported. Invasive device-associated infections were associated with specific pathogens. Although device-associated site-specific infection rates are currently our most useful rates for performing comparisons between ICUs, the considerable variation in these rates between ICUs indicates the need for further risk adjustment.
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                Author and article information

                Contributors
                Dinesh Subedi:
                ORCID: http://orcid.org/0000-0002-1357-9520
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Ajay Kumar Vijay: Role: SupervisionRole: Writing – review & editing
                Gurjeet Singh Kohli: Role: Data curation
                Scott A. Rice: Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Mark Willcox: Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Abdelwahab Omri: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 28 September 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 9
                Electronic Location Identifier: e0204936
                Affiliations
                [1 ] School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
                [2 ] The Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore
                [3 ] The School of Biological Sciences, Nanyang Technological University, Singapore
                [4 ] The ithree institute, The University of Technology Sydney, Sydney NSW Australia
                Laurentian, CANADA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1357-9520
                Article
                Publisher ID: PONE-D-18-22078
                DOI: 10.1371/journal.pone.0204936
                PMC ID: 6161911
                PubMed ID: 30265709
                SO-VID: b797d2d7-7c26-442c-b698-2f3946d817eb
                Copyright © © 2018 Subedi et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 July 2018
                Date accepted : 17 September 2018
                Page count
                Figures: 2, Tables: 4, Pages: 14
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Microbial Control
                Subject: Antimicrobial Resistance
                Subject: Antibiotic Resistance
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Antimicrobial Resistance
                Subject: Antibiotic Resistance
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Medical Microbiology
                Subject: Microbial Pathogens
                Subject: Bacterial Pathogens
                Subject: Pseudomonas Aeruginosa
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Pathogens
                Subject: Microbial Pathogens
                Subject: Bacterial Pathogens
                Subject: Pseudomonas Aeruginosa
                Subject: Biology and Life Sciences
                Subject: Organisms
                Subject: Bacteria
                Subject: Pseudomonas
                Subject: Pseudomonas Aeruginosa
                Subject: Medicine and Health Sciences
                Subject: Clinical Genetics
                Subject: Genetic Diseases
                Subject: Autosomal Recessive Diseases
                Subject: Cystic Fibrosis
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Fibrosis
                Subject: Cystic Fibrosis
                Subject: Medicine and Health Sciences
                Subject: Pulmonology
                Subject: Cystic Fibrosis
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Mutation
                Subject: Point Mutation
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drugs
                Subject: Antimicrobials
                Subject: Antibiotics
                Subject: Biology and Life Sciences
                Subject: Microbiology
                Subject: Microbial Control
                Subject: Antimicrobials
                Subject: Antibiotics
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Mutation
                Subject: Mutant Strains
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Types
                Subject: Regulator Genes
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information file. All genomes are available from the NCBI database under bio-project accession number PRJNA431326.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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