scholarly journals Pumping out biocides – cause for concern

2010 ◽  
Vol 31 (4) ◽  
pp. 178
Author(s):  
Karl A Hassan ◽  
Sylvia Baltzer ◽  
Ian Paulsen ◽  
Melissa Brown
Keyword(s):  
Active Sites ◽  
Resistance Mechanisms ◽  
Opportunistic Pathogens ◽  
Research Groups ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Active Efflux ◽  
Resistance Determinants ◽  
Intracellular Targets ◽  
Ammonium Compounds

Bacteria employ a number of resistance mechanisms against antimicrobials, commonly including target site modification, antimicrobial degradation and active efflux. Of these mechanisms, efflux is unique in that a single efflux system can confer resistance to a remarkably broad range of structurally dissimilar antibiotics and biocides that have different intracellular targets and modes of action. For example, in the opportunistic pathogens Staphylococcus aureus and Acinetobacter baumannii, single multidrug efflux systems facilitate the extrusion of agents as broad and diverse as quaternary ammonium compounds, intercalating dyes, diamidines, biguanidines, anionic detergents, aminoglycosides, ?-lactams, chloramphenicol, tetracyclines, trimethoprim and fluoroquinolones (Table 1). This promiscuity of substrates, coupled with the genetic linkage of exporter genes with other resistance determinants on transferable elements such as plasmids, raises the possibility of cross and co-resistance to biocides and antibiotics. Furthermore, data generated by our and other research groups clearly demonstrate a remarkable propensity of multidrug efflux systems to bind new substrates following only minor amino acid changes to their active sites.

scholarly journals Genomic Insights into Drug Resistance Determinants in Cedecea neteri, A Rare Opportunistic Pathogen

2021 ◽  
Vol 9 (8) ◽  
pp. 1741
Author(s):  
Dorothea K. Thompson ◽  
Stephen M. Sharkady
Keyword(s):  
Drug Resistance ◽  
Sequence Data ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Whole Genome Sequence ◽  
Multidrug Efflux ◽  
Resistance Determinants ◽  
Multidrug Efflux Pumps ◽  
Novel Variant ◽  
Immunocompromised Hosts

Cedecea, a genus in the Enterobacteriaceae family, includes several opportunistic pathogens reported to cause an array of sporadic acute infections, most notably of the lung and bloodstream. One species, Cedecea neteri, is associated with cases of bacteremia in immunocompromised hosts and has documented resistance to different antibiotics, including β-lactams and colistin. Despite the potential to inflict serious infections, knowledge about drug resistance determinants in Cedecea is limited. In this study, we utilized whole-genome sequence data available for three environmental strains (SSMD04, M006, ND14a) of C. neteri and various bioinformatics tools to analyze drug resistance genes in this bacterium. All three genomes harbor multiple chromosome-encoded β-lactamase genes. A deeper analysis of β-lactamase genes in SSMD04 revealed four metallo-β-lactamases, a novel variant, and a CMY/ACT-type AmpC putatively regulated by a divergently transcribed AmpR. Homologs of known resistance-nodulation-cell division (RND)-type multidrug efflux pumps such as OqxB, AcrB, AcrD, and MdtBC were also identified. Genomic island prediction for SSMD04 indicated that tolC, involved in drug and toxin export across the outer membrane of Gram-negative bacteria, was acquired by a transposase-mediated genetic transfer mechanism. Our study provides new insights into drug resistance mechanisms of an environmental microorganism capable of behaving as a clinically relevant opportunistic pathogen.

scholarly journals Role of the Multidrug Efflux System MexXY in the Emergence of Moderate Resistance to Aminoglycosides among Pseudomonas aeruginosa Isolates from Patients with Cystic Fibrosis

2004 ◽  
Vol 48 (5) ◽  
pp. 1676-1680 ◽  
Author(s):  
Christelle Vogne ◽  
Julio Ramos Aires ◽  
Christiane Bailly ◽  
Didier Hocquet ◽  
Patrick Plésiat
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Fold Increase ◽  
Resistant Bacteria ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Active Efflux ◽  
Moderate Resistance ◽  
Moderately Resistant

ABSTRACT This study investigates the role of active efflux system MexXY in the emergence of aminoglycoside (AG) resistance among cystic fibrosis (CF) isolates of Pseudomonas aeruginosa. Three genotypically related susceptible and resistant (S/R) bacterial pairs and three other AG-resistant CF strains were compared to four non-CF strains moderately resistant to AGs. As demonstrated by immunoblot experiments, pump MexY was strongly overproduced in all of the resistant bacteria. This MexXY upregulation was associated with a 2- to 16-fold increase in the MICs of AGs in the S/R pairs and lower intracellular accumulation of dihydrostreptomycin. Alterations in mexZ, the repressor gene of operon mexXY, were found in all of the AG-resistant CF isolates and in one non-CF strain. Complementation of these bacteria with a plasmid-borne mexZ gene dramatically reduced the MICs of AGs, thus highlighting the role played by MexXY in the development of moderate resistance in CF patients. In contrast, complementation of the three non-CF strains showing wild-type mexZ genes left residual levels of resistance to AGs. These data indicate that a locus different from mexZ may be involved in overproduction of MexXY and that other nonenzymatic mechanisms contribute to AG resistance in P. aeruginosa.

Conservation of the multidrug resistance efflux gene oprM in Pseudomonas aeruginosa.

1997 ◽  
Vol 41 (4) ◽  
pp. 853-856 ◽  
Author(s):  
N Bianco ◽  
S Neshat ◽  
K Poole
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Pseudomonas Syringae ◽  
Genomic Dna ◽  
Resistance Mechanisms ◽  
Pseudomonas Chlororaphis ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Multidrug Resistance Gene ◽  
Multidrug Efflux System

An intragenic probe derived from the multidrug resistance gene oprM hybridized with genomic DNA from all 20 serotypes of Pseudomonas aeruginosa and from all 34 environmental and clinical isolates tested, indicating that the MexA-MexB-OprM multidrug efflux system is highly conserved in this organism. The oprM probe also hybridized with genomic DNA from Pseudomonas aureofaciens, Pseudomonas chlororaphis, Pseudomonas syringae, Burkholderia pseudomallei, and Pseudomonas putida, suggesting that efflux-mediated multidrug resistance mechanisms may be somewhat broadly distributed.

scholarly journals Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay

2001 ◽  
Vol 45 (7) ◽  
pp. 1964-1971 ◽  
Author(s):  
Kiyomi Okamoto ◽  
Naomasa Gotoh ◽  
Takeshi Nishino
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Outer Membrane ◽  
Laboratory Strain ◽  
Resistance Mechanisms ◽  
Efflux System ◽  
Intrinsic Resistance ◽  
Active Efflux ◽  
Membrane Barrier ◽  
Susceptibility Tests ◽  
Almost All

ABSTRACT Pseudomonas aeruginosa exhibits high intrinsic resistance to penem antibiotics such as faropenem, ritipenem, AMA3176, sulopenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC β-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encodedEscherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC β-lactamase, are the main mechanisms involved in the high intrinsic penem resistance of PAO1. However, reducing the high intrinsic penem resistance of PAO1 to the same level as that of penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC β-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faropenem were about 1.8- and 1.5-fold lower, than the respective affinity for imipenem. Loss of the outer membrane barrier, MexAB, and AmpC β-lactamase increased the susceptibility of PAO1 to almost all penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imipenem. Thus, it is suggested that the high intrinsic penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC β-lactamase but not from the lower affinity of PBPs for penems.

scholarly journals Differential selection of multidrug efflux systems by quinolones in Pseudomonas aeruginosa.

1997 ◽  
Vol 41 (11) ◽  
pp. 2540-2543 ◽  
Author(s):  
T Köhler ◽  
M Michea-Hamzehpour ◽  
P Plesiat ◽  
A L Kahr ◽  
J C Pechere
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Fluorine Atom ◽  
Efflux Pump ◽  
Resistance Mechanisms ◽  
Multidrug Efflux ◽  
Efflux System ◽  
In Vitro Exposure ◽  
Structural Determinant ◽  
Selection Of

Resistance mechanisms selected after in vitro exposure to 12 quinolones were analyzed for Pseudomonas aeruginosa. Efflux-type mutants were predominant. Quinolones differed in their ability to select a particular efflux system. While the newer fluoroquinolones favored the MexCD-OprJ system, the older quinolones selected exclusively the MexEF-OprN or MexAB-OprM systems. A protonable C-7 substituent in combination with a C-6 fluorine atom is a structural determinant of quinolones involved in efflux pump substrate specificity.

scholarly journals An Application of Imipenem Discs or P. aeruginosa ATCC 27853 Reference Strain Increases Sensitivity of Carbapenem Inactivation Method for Non-Fermenting Gram-Negative Bacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 875
Author(s):  
Tomasz Bogiel ◽  
Mateusz Rzepka ◽  
Eugenia Gospodarek-Komkowska
Keyword(s):  
Human Population ◽  
Reference Strain ◽  
Resistance Mechanisms ◽  
Gram Negative Bacteria ◽  
Opportunistic Pathogens ◽  
Beta Lactams ◽  
Gram Negative ◽  
E Coli ◽  
Human Infections ◽  
Reliable Diagnostic Method

Non-fermenting Gram-negative rods are one of the most commonly isolated bacteria from human infections. These microorganisms are typically opportunistic pathogens that pose a serious threat to public health due to possibility of transmission in the human population. Resistance to beta-lactams, due to carbapenemases synthesis, is one of the most important antimicrobial resistance mechanisms amongst them. The aim of this study was to evaluate the usefulness of the Carbapenem Inactivation Method (CIM), and its modifications, for the detection of carbapenemase activity amongst non-fermenting Gram-negative rods. This research involved 81 strains of Gram-negative rods. Of the tested strains, 55 (67.9%) synthesized carbapenemases. For non-fermenting rods, 100% sensitivity and specificity was obtained in the version of the CIM test using imipenem discs and E. coli ATCC 25922 strain. The CIM test allows for differentiation of carbapenems resistance mechanisms resulting from carbapenemase synthesis from other resistance types. It is a reliable diagnostic method for the detection of carbapenemase activity amongst non-fermenting Gram-negative rods. Application of imipenem discs and P. aeruginosa ATCC 27853 reference strain increases CIM results sensitivity, while imipenem discs and E. coli ATCC 25922 strain use maintains full precision of the test for non-fermenting rods.

scholarly journals Resistance Mechanisms of Multiresistant Pseudomonas aeruginosa Strains from Germany and Correlation with Hypermutation

2007 ◽  
Vol 51 (11) ◽  
pp. 4062-4070 ◽  
Author(s):  
B. Henrichfreise ◽  
I. Wiegand ◽  
W. Pfister ◽  
B. Wiedemann
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Type Ii ◽  
Mechanisms Of Resistance ◽  
Resistance Determinants ◽  
Class 1 ◽  
Mutator Strains ◽  
Multiresistant Strains

ABSTRACT In this study, we analyzed the mechanisms of multiresistance for 22 clinical multiresistant and clonally different Pseudomonas aeruginosa strains from Germany. Twelve and 10 strains originated from cystic fibrosis (CF) and non-CF patients, respectively. Overproduction of the efflux systems MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM was studied. Furthermore, loss of OprD, alterations in type II topoisomerases, AmpC overproduction, and the presence of 25 acquired resistance determinants were investigated. The presence of a hypermutation phenotype was also taken into account. Besides modifications in GyrA (91%), the most frequent mechanisms of resistance were MexXY-OprM overproduction (82%), OprD loss (82%), and AmpC overproduction (73%). Clear differences between strains from CF and non-CF patients were found: numerous genes coding for aminoglycoside-modifying enzymes and located, partially in combination with β-lactamase genes, in class 1 integrons were found only in strains from non-CF patients. Furthermore, multiple modifications in type II topoisomerases conferring high quinolone resistance levels and overexpression of MexAB-OprM were exclusively detected in multiresistant strains from non-CF patients. Correlations of the detected phenotypes and resistance mechanisms revealed a great impact of efflux pump overproduction on multiresistance in P. aeruginosa. Confirming previous studies, we found that additional, unknown chromosomally mediated resistance mechanisms remain to be determined. In our study, 11 out of 12 strains and 3 out of 10 strains from CF patients and non-CF patients, respectively, were hypermutable. This extremely high proportion of mutator strains should be taken into consideration for the treatment of multiresistant P. aeruginosa.

BmeRABC5 Is a Multidrug Efflux System That Can Confer Metronidazole Resistance inBacteroides fragilis

2007 ◽  
Vol 13 (2) ◽  
pp. 96-101 ◽  
Author(s):  
Lilian Pumbwe ◽  
Abraham Chang ◽  
Rachel L. Smith ◽  
Hannah M. Wexler
Keyword(s):  
Multidrug Efflux ◽  
Efflux System ◽  
Metronidazole Resistance ◽  
Multidrug Efflux System

scholarly journals Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

2013 ◽  
Vol 7 (1) ◽  
pp. 34-52 ◽  
Author(s):  
Christina Kourtesi ◽  
Anthony R Ball ◽  
Ying-Ying Huang ◽  
Sanjay M Jachak ◽  
D Mariano A Vera ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Major Theme ◽  
Clinical Implementation ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Development Path ◽  
Microbial Infections ◽  
Efflux Pump Inhibitors ◽  
Shed Light

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

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