scholarly journals Rapid Killing of Acinetobacter baumannii by Polymyxins Is Mediated by a Hydroxyl Radical Death Pathway

2012 ◽  
Vol 56 (11) ◽  
pp. 5642-5649 ◽  
Author(s):  
Timothy R. Sampson ◽  
Xiang Liu ◽  
Max R. Schroeder ◽  
Colleen S. Kraft ◽  
Eileen M. Burd ◽  
...  
Keyword(s):  
Hydroxyl Radical ◽  
Acinetobacter Baumannii ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Alternative Mechanism ◽  
Content Type ◽  
Radical Production ◽  
Clinically Significant

ABSTRACTAcinetobacter baumanniiis an opportunistic pathogen that is a cause of clinically significant nosocomial infections. Increasingly, clinical isolates ofA. baumanniiare extensively resistant to numerous antibiotics, and the use of polymyxin antibiotics against these infections is often the final treatment option. Historically, the polymyxins have been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism based on data demonstrating that polymyxins induce rapid cell death through hydroxyl radical production. Supporting this notion, we found that inhibition of radical production delays the ability of polymyxins to killA. baumannii. Notably, we demonstrate that this mechanism of killing occurs in multidrug-resistant clinical isolates ofA. baumanniiand that this response is not induced in a polymyxin-resistant isolate. This study is the first to demonstrate that polymyxins induce rapid killing ofA. baumanniiand other Gram-negatives through hydroxyl radical production. This significantly augments our understanding of the mechanism of polymyxin action, which is critical knowledge toward the development of adjunctive therapies, particularly given the increasing necessity for treatment with these antibiotics in the clinical setting.

scholarly journals In Vitro Activity of Sulbactam-Durlobactam against Acinetobacter baumannii-calcoaceticus Complex Isolates Collected Globally in 2016 and 2017

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Sarah M. McLeod ◽  
Samir H. Moussa ◽  
Meredith A. Hackel ◽  
Alita A. Miller
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Single Amino Acid ◽  
Content Type ◽  
Level Of Activity ◽  
Severe Infections ◽  
Sources Of Infection

ABSTRACT Acinetobacter baumannii-calcoaceticus complex (ABC) organisms cause severe infections that are difficult to treat due to preexisting antibiotic resistance. Sulbactam-durlobactam (formerly sulbactam-ETX2514) (SUL-DUR) is a β-lactam–β-lactamase inhibitor combination antibiotic designed to treat serious infections caused by ABC organisms, including multidrug-resistant (MDR) strains. The in vitro antibacterial activities of SUL-DUR and comparator agents were determined by broth microdilution against 1,722 clinical isolates of ABC organisms collected in 2016 and 2017 from 31 countries across Asia/South Pacific, Europe, Latin America, the Middle East, and North America. Over 50% of these isolates were resistant to carbapenems. Against this collection of global isolates, SUL-DUR had a MIC50/MIC90 of 1/2 μg/ml compared to a MIC50/MIC90 of 8/64 μg/ml for sulbactam alone. This level of activity was found to be consistent across organisms, regions, sources of infection, and subsets of resistance phenotypes, including MDR and extensively drug-resistant isolates. The SUL-DUR activity was superior to those of the tested comparators, with only colistin having similar potency. Whole-genome sequencing of the 39 isolates (2.3%) with a SUL-DUR MIC of >4 μg/ml revealed that these strains encoded either the metallo-β-lactamase NDM-1, which durlobactam does not inhibit, or single amino acid substitutions near the active site of penicillin binding protein 3 (PBP3), the primary target of sulbactam. In summary, SUL-DUR demonstrated potent antibacterial activity against recent, geographically diverse clinical isolates of ABC organisms, including MDR isolates.

scholarly journals Characterization of the Enterobacter Phage vB_EclM_CIP9

2020 ◽  
Vol 9 (13) ◽  
Author(s):  
Klara Wang ◽  
Marielou G. Tamayo ◽  
Tiffany V. Penner ◽  
Bradley W. M. Cook ◽  
Deborah A. Court ◽  
...  
Keyword(s):  
Enterobacter Cloacae ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Open Reading Frames ◽  
Resistant Isolate ◽  
Content Type ◽  
Hospital Acquired Infections ◽  
Hospital Acquired ◽  
Reading Frames

Enterobacter cloacae is an opportunistic pathogen that causes hospital-acquired infections in immunocompromised patients. Here, we describe vB_EclM_CIP9, a novel Enterobacter phage that infects a multidrug-resistant isolate of E. cloacae. Phage vB_EclM_CIP9 is a myovirus that has a 174,924-bp genome, with 296 predicted open reading frames.

scholarly journals Draft Genome Sequences of Clinical Isolates of Multidrug-Resistant Acinetobacter baumannii

2017 ◽  
Vol 5 (5) ◽  
Author(s):  
Keesha E. Erickson ◽  
Nancy E. Madinger ◽  
Anushree Chatterjee
Keyword(s):  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Draft Genome ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Genome Sequences ◽  
Content Type ◽  
University Of Colorado ◽  
The University

ABSTRACT We report here the draft genome sequences of two clinically isolated Acinetobacter baumannii strains. These samples were obtained from patients at the University of Colorado Hospital in 2007 and 2013 and encode an estimated 20 and 13 resistance genes, respectively.

scholarly journals Unique Structural Modifications Are Present in the Lipopolysaccharide from Colistin-Resistant Strains of Acinetobacter baumannii

2013 ◽  
Vol 57 (10) ◽  
pp. 4831-4840 ◽  
Author(s):  
Mark R. Pelletier ◽  
Leila G. Casella ◽  
Jace W. Jones ◽  
Mark D. Adams ◽  
Daniel V. Zurawski ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Lipid A ◽  
Opportunistic Pathogen ◽  
Structure Characterization ◽  
Resistant Isolate ◽  
Patient Treatment ◽  
Cationic Antimicrobial Peptide ◽  
Content Type ◽  
Lipid A Structure ◽  
Resistant Strains

ABSTRACTAcinetobacter baumanniiis a nosocomial opportunistic pathogen that can cause severe infections, including hospital-acquired pneumonia, wound infections, and sepsis. Multidrug-resistant (MDR) strains are prevalent, further complicating patient treatment. Due to the increase in MDR strains, the cationic antimicrobial peptide colistin has been used to treatA. baumanniiinfections. Colistin-resistant strains ofA. baumanniiwith alterations to the lipid A component of lipopolysaccharide (LPS) have been reported; specifically, the lipid A structure was shown to be hepta-acylated with a phosphoethanolamine (pEtN) modification present on one of the terminal phosphate residues. Using a tandem mass spectrometry platform, we provide definitive evidence that the lipid A isolated from colistin-resistantA. baumanniiMAC204 LPS contains a novel structure corresponding to a diphosphoryl hepta-acylated lipid A structure with both pEtN and galactosamine (GalN) modifications. To correlate our structural studies with clinically relevant samples, we characterized colistin-susceptible and -resistant isolates obtained from patients. These results demonstrated that the clinical colistin-resistant isolate had the same pEtN and GalN modifications as those seen in the laboratory-adaptedA. baumanniistrain MAC204. In summary, this work has shown complete structure characterization including the accurate assignment of acylation, phosphorylation, and glycosylation of lipid A fromA. baumannii, which are important for resistance to colistin.

scholarly journals Thiostrepton Hijacks Pyoverdine Receptors To Inhibit Growth ofPseudomonas aeruginosa

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Michael R. M. Ranieri ◽  
Derek C. K. Chan ◽  
Luke N. Yaeger ◽  
Madeleine Rudolph ◽  
Sawyer Karabelas-Pittman ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
23S Rrna ◽  
Dependent Manner ◽  
Peptide Antibiotics ◽  
Iron Starvation ◽  
Gram Negative ◽  
Content Type

ABSTRACTPseudomonas aeruginosais a biofilm-forming opportunistic pathogen and is intrinsically resistant to many antibiotics. In a high-throughput screen for molecules that modulate biofilm formation, we discovered that the thiopeptide antibiotic thiostrepton (TS), which is considered to be inactive against Gram-negative bacteria, stimulatedP. aeruginosabiofilm formation in a dose-dependent manner. This phenotype is characteristic of exposure to antimicrobial compounds at subinhibitory concentrations, suggesting that TS was active againstP. aeruginosa. Supporting this observation, TS inhibited the growth of a panel of 96 multidrug-resistant (MDR)P. aeruginosaclinical isolates at low-micromolar concentrations. TS also had activity againstAcinetobacter baumanniiclinical isolates. The expression of Tsr, a 23S rRNA-modifying methyltransferase from TS producerStreptomyces azureus, intransconferred TS resistance, confirming that the drug acted via its canonical mode of action, inhibition of ribosome function. The deletion of oligopeptide permease systems used by other peptide antibiotics for uptake failed to confer TS resistance. TS susceptibility was inversely proportional to iron availability, suggesting that TS exploits uptake pathways whose expression is increased under iron starvation. Consistent with this finding, TS activity againstP. aeruginosaandA. baumanniiwas potentiated by the FDA-approved iron chelators deferiprone and deferasirox and by heat-inactivated serum. Screening ofP. aeruginosamutants for TS resistance revealed that it exploits pyoverdine receptors FpvA and FpvB to cross the outer membrane. We show that the biofilm stimulation phenotype can reveal cryptic subinhibitory antibiotic activity, and that TS has activity against select multidrug-resistant Gram-negative pathogens under iron-limited growth conditions, similar to those encountered at sites of infection.

scholarly journals Novel Aminoglycoside Resistance Transposons and Transposon-Derived Circular Forms Detected in Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

2016 ◽  
Vol 60 (3) ◽  
pp. 1801-1818 ◽  
Author(s):  
Nabil Karah ◽  
Chinmay Kumar Dwibedi ◽  
Karin Sjöström ◽  
Petra Edquist ◽  
Anders Johansson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Point Mutations ◽  
Antibiotic Resistance Genes ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Carbapenem Resistant

Acinetobacter baumanniihas emerged as an important opportunistic pathogen equipped with a growing number of antibiotic resistance genes. Our study investigated the molecular epidemiology and antibiotic resistance features of 28 consecutive carbapenem-resistant clinical isolates ofA. baumanniicollected throughout Sweden in 2012 and 2013. The isolates mainly belonged to clonal complexes (CCs) with an extensive international distribution, such as CC2 (n= 16) and CC25 (n= 7). Resistance to carbapenems was related toblaOXA-23(20 isolates),blaOXA-24/40-like(6 isolates),blaOXA-467(1 isolate), and ISAba1-blaOXA-69(1 isolate). Ceftazidime resistance was associated withblaPER-7in the CC25 isolates. Two classical point mutations were responsible for resistance to quinolones in all the isolates. Isolates with high levels of resistance to aminoglycosides carried the 16S rRNA methylasearmAgene. The isolates also carried a variety of genes encoding aminoglycoside-modifying enzymes. Several novel structures involved in aminoglycoside resistance were identified, including Tn6279, ΔTn6279, Ab-ST3-aadB, and different assemblies of Tn6020and TnaphA6. Importantly, a number of circular forms related to the IS26or ISAba125composite transposons were detected. The frequent occurrence of these circular forms in the populations of several isolates indicates a potential role of these circular forms in the dissemination of antibiotic resistance genes.

scholarly journals Globally Expanding Carbapenemase Finally Appears in Spain: Nosocomial Outbreak of Acinetobacter baumannii Producing Plasmid-Encoded OXA-23 in Barcelona, Spain

2013 ◽  
Vol 57 (10) ◽  
pp. 5155-5157 ◽  
Author(s):  
Noraida Mosqueda ◽  
Paula Espinal ◽  
Clara Cosgaya ◽  
Sergio Viota ◽  
Virginia Plasensia ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Molecular Characterization ◽  
Multidrug Resistant ◽  
Sequence Type ◽  
Clinical Isolates ◽  
Nosocomial Outbreak ◽  
Content Type ◽  
Hospital Outbreak

ABSTRACTResistance ofAcinetobacter baumanniiclinical isolates to carbapenems is on the rise worldwide mainly in association with the production of OXA-23. Until recently, however, OXA-23 was absent in Spain. In this work, we report the molecular characterization of a hospital outbreak of OXA-23-producingA. baumanniiin Barcelona caused by a multidrug-resistant (MDR) clone belonging to international clone IC-II/sequence type ST85 between October 2010 and May 2011.blaOXA-23was carried in a plasmid of 90 kb and located within the composite transposon Tn2006.

scholarly journals Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Arnaud Riat ◽  
Jérôme Plojoux ◽  
Katia Gindro ◽  
Jacques Schrenzel ◽  
Dominique Sanglard
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Clinical Settings ◽  
Content Type ◽  
Azole Antifungals ◽  
First Time

ABSTRACT Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target ( cyp51A ). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR 34 /L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR 34 /L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment.

scholarly journals GigC, a LysR Family Transcription Regulator, Is Required for Cysteine Metabolism and Virulence in Acinetobacter baumannii

2020 ◽  
Vol 89 (1) ◽  
pp. e00180-20
Author(s):  
Michael J. Gebhardt ◽  
Daniel M. Czyz ◽  
Shweta Singh ◽  
Daniel V. Zurawski ◽  
Lev Becker ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
Resistant Isolate ◽  
Infection Model ◽  
Content Type ◽  
Transcription Regulator ◽  
Nutritional Immunity ◽  
Metabolic Products ◽  
Lysr Family

ABSTRACTA critical facet of mammalian innate immunity involves the hosts’ attempts to sequester and/or limit the availability of key metabolic products from pathogens. For example, nutritional immunity encompasses host approaches to limit the availability of key heavy metal ions such as zinc and iron. Previously, we identified several hundred genes in a multidrug-resistant isolate of Acinetobacter baumannii that are required for growth and/or survival in the Galleria mellonella infection model. In the present study, we further characterize one of these genes, a LysR family transcription regulator that we previously named GigC. We show that mutant strains lacking gigC have impaired growth in the absence of the amino acid cysteine and that gigC regulates the expression of several genes involved in the sulfur assimilation and cysteine biosynthetic pathways. We further show that cells harboring a deletion of the gigC gene are attenuated in two murine infection models, suggesting that the GigC protein, likely through its regulation of the cysteine biosynthetic pathway, plays a key role in the virulence of A. baumannii.

scholarly journals Next Generation of Tn7-Based Single-Copy Insertion Elements for Use in Multi- and Pan-Drug-Resistant Strains of Acinetobacter baumannii

2019 ◽  
Vol 85 (11) ◽  
Author(s):  
Kaleigh Ducas-Mowchun ◽  
P. Malaka De Silva ◽  
Leandro Crisostomo ◽  
Dinesh M. Fernando ◽  
Tzu-Chiao Chao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acinetobacter Baumannii ◽  
Single Copy ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Drug Resistant ◽  
Content Type ◽  
Flp Recombinase ◽  
Fluorescent Markers ◽  
Selection Markers

ABSTRACT The purpose of this study was to create single-copy gene expression systems for use in genomic manipulations of multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates of Acinetobacter baumannii. In this study, mini-Tn7 vectors with zeocin and apramycin selection markers were created by cloning the ble and aac(3)-IV genes, respectively, enabling either inducible gene expression (pUC18T-mini-Tn7T-Zeo-LAC and pUC18T-mini-Tn7T-Apr-LAC) or expression from native or constitutive promoters (pUC18T-mini-Tn7T-Zeo and pUC18T-mini-Tn7T-Apr). The selection markers of these plasmids are contained within a Flp recombinase target (FRT) cassette, which can be used to obtain unmarked mini-Tn7 insertions upon introduction of a source of Flp recombinase. To this end, site-specific excision vectors pFLP2A and pFLP2Z (containing apramycin and zeocin selection markers, respectively) were created in this study as an accessory to the mini-Tn7 vectors described above. Combinations of these novel mini-Tn7 plasmids and their compatible pFLP2Z or pFLP2A accessory plasmid were used to generate unmarked insertions in MDR clinical isolates of A. baumannii. In addition, several fluorescent markers were cloned and inserted into MDR and XDR clinical isolates of A. baumannii via these apramycin and zeocin mini-Tn7 constructs to demonstrate their application. IMPORTANCE Acinetobacter baumannii is a high-priority pathogen for which research on mechanisms of resistance and virulence is a critical need. Commonly used antibiotic selection markers are not suitable for use in MDR and XDR isolates of A. baumannii due to the high antibiotic resistance of these isolates, which poses a barrier to the study of this pathogen. This study demonstrates the practical potential of using apramycin and zeocin mini-Tn7- and Flp recombinase-encoded constructs to carry out genomic manipulations in clinical isolates of A. baumannii displaying MDR and XDR phenotypes.

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