scholarly journals The H-NS Regulator Plays a Role in the Stress Induced by Carbapenemase Expression in Acinetobacter baumannii

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Fanny Huang ◽  
Noelle Fitchett ◽  
Chelsea Razo-Gutierrez ◽  
Casin Le ◽  
Jasmine Martinez ◽  
...  
Keyword(s):  
Stress Response ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Dna Damaging Agents ◽  
Envelope Stress ◽  
Evolutionary Advantage

ABSTRACT Disruption of the histone-like nucleoid structuring protein (H-NS) was shown to affect the ability of Gram-negative bacteria to regulate genes associated with virulence, persistence, stress response, quorum sensing, biosynthesis pathways, and cell adhesion. Here, we used the expression of metallo-β-lactamases (MBLs), known to elicit envelope stress by the accumulation of toxic precursors in the periplasm, to interrogate the role of H-NS in Acinetobacter baumannii, together with other stressors. Using a multidrug-resistant A. baumannii strain, we observed that H-NS plays a role in alleviating the stress triggered by MBL toxic precursors and counteracts the effect of DNA-damaging agents, supporting its role in stress response. IMPORTANCE Carbapenem-resistant A. baumannii (CRAB) is recognized as one of the most threatening Gram-negative bacilli. H-NS is known to play a role in controlling the transcription of a variety of different genes, including those associated with the stress response, persistence, and virulence. In the present work, we uncovered a link between the role of H-NS in the A. baumannii stress response and its relationship with the envelope stress response and resistance to DNA-damaging agents. Overall, we posit a new role of H-NS, showing that H-NS serves to endure envelope stress and could also be a mechanism that alleviates the stress induced by MBL expression in A. baumannii. This could be an evolutionary advantage to further resist the action of carbapenems.

scholarly journals The H-NS regulator plays a role in the stress induced by carbapenemase expression in Acinetobacter baumannii

2020 ◽  
Author(s):  
Fanny Huang ◽  
Noelle Fitchett ◽  
Chelsea Razo-Gutierrez ◽  
Casin Le ◽  
Grace Ra ◽  
...  
Keyword(s):  
Stress Response ◽  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Toxic Species ◽  
Carbapenem Resistant ◽  
Dna Damaging Agents ◽  
Envelope Stress ◽  
Evolutionary Advantage

AbstractDisruption of the histone-like nucleoid structuring protein (H-NS) was shown to affect the ability for Gram-negative bacteria to regulate genes associated with virulence, persistence, stress response, quorum sensing, biosynthesis pathways and cell adhesion. Here, we used the expression of metallo-β-lactamases (MBLs) known to elicit envelope stress by the accumulation of toxic species in the periplasm to interrogate the role of H-NS in Acinetobacter baumannii, together with other stressors. Using a multidrug-resistant A. baumannii, we observed that H-NS plays a role in alleviating the stress triggered by MBL toxic precursors and counteract the effect of DNA-damaging agents, supporting its role in stress response.ImportanceCarbapenem-resistant A. baumannii (CRAB) is recognized as one of the most threatening gram-negative bacilli. H-NS is known to play a role in controlling the transcription of a variety of different genes, including those associated with stress response, persistence and virulence. In the present work, we uncovered a link between the role of H-NS in the A. baumannii stress response and its relationship with the envelope stress response and resistance to DNA-damaging agents. Overall, we posit a new role of H-NS, showing that H-NS serves to endure envelope stress that could also be a mechanism that alleviates the stress induced by MBL expression in A. baumannii. This could be an evolutionary advantage to further resist the action of carbapenems.

scholarly journals Cefiderocol Resistance in Acinetobacter baumannii: Roles of β-Lactamases, Siderophore Receptors, and Penicillin Binding Protein 3

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Saquib Malik ◽  
Monica Kaminski ◽  
David Landman ◽  
John Quale
Keyword(s):  
Acinetobacter Baumannii ◽  
Binding Protein ◽  
Receptor Gene ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Penicillin Binding Protein ◽  
Gram Negative ◽  
Content Type ◽  
Siderophore Receptors

ABSTRACT Cefiderocol is a siderophore cephalosporin active against many multidrug-resistant (MDR) Gram-negative pathogens. We examined the resistance mechanisms in 12 Acinetobacter baumannii strains with cefiderocol MICs ranging from ≤0.03 to >32 μg/ml. Cefiderocol resistance could not be explained by β-lactamase activity. Cefiderocol resistance was associated with reduced expression of the siderophore receptor gene pirA. Mutations involving PBP3 may have contributed to resistance in one strain. Additional studies are needed to assess the role of other siderophore receptors.

scholarly journals 1297. In-Vitro Antibacterial Activities of Cefiderocol (S-649266) Alone and With the Addition of Beta-Lactamase Inhibitors Against Multidrug-resistant Acinetobacter baumannii

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S663-S663
Author(s):  
Jacinda C Abdul-Mutakabbir ◽  
Logan Nguyen ◽  
Philip Maassen ◽  
Kyle Stamper ◽  
Razieh Kebriaei ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Beta Lactamase ◽  
Gram Negative ◽  
Carbapenem Resistant ◽  
Mueller Hinton ◽  
Fold Reduction

Abstract Background Multidrug-resistant (MDR) infections caused by Acinetobacter baumannii continue to pose a serious public health threat. Cefiderocol (CFDC) is a new parental siderophore cephalosporin that has displayed potent activity against Gram-negative bacteria, more specifically non-fermenting Gram-negative bacilli, including A. baumannii. Although uncommon, elevated minimum inhibitory concentrations (MICs) to CFDC have been reported, when tested against A. baumannii isolates, in-vitro. The addition of beta-lactamase inhibitors has been shown to be successful in decreasing elevated CFDC MICs. The evaluation of sulbactam (SUL), tazobactam (TAZO), or clavulanic acid (CLAV) in addition to CFDC against A. baumannii isolates with elevated CFDC MICs, has yet to be reported. The objective of this study was to evaluate the activity of several beta-lactamase inhibitors in combination with CFDC against A. baumannii strains with high CFDC MICs. Methods One hundred and fifty carbapenem-resistant A. baumannii strains were selected from the Anti-infective Research Laboratory. MIC susceptibility testing was performed for all of the strains via broth microdilution (BMD). Seven strains that exhibited elevated CFDC MICs,16-32 mg/L, were assessed via BMD, with the addition of the following beta-lactamase inhibitors: TAZO, SUL, AVI, and CLAV to CFDC. All in-vitro testing for CFDC was completed with the use of iron-depleted cation-adjusted Mueller-Hinton broth to ensure the induction of bacterial iron transporters per manufacturer standards. Results A decline in elevated CFDC MIC values was observed in six of the seven A. baumannii strains, with the addition of each beta-lactamase inhibitor. AVI showed the most potent activity when added to CFDC, with an average 28- fold reduction in MIC values observed. SUL and CLAV produced similar fold reductions in the MIC values with an average 20-fold reduction observed with the addition of either agent to FDC. The addition of TAZO to CFDC also presented with a decline in MIC values, with an average 7-fold-reduction observed. Cefiderocol (CFDC) strains with MICs of 16-32 mg/l plus Beta-Lactamase Inhibitors Conclusion The addition of several beta-lactamase inhibitors to CFDC has shown promise in decreasing elevated CFDC MICs. Further research is warranted to determine the role of BLIs on CFDC activity. Disclosures Michael J. Rybak, PharmD, MPH, PhD, Paratek (Grant/Research Support)

scholarly journals In VitroActivity of RX-P873 against Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii

2015 ◽  
Vol 59 (4) ◽  
pp. 2280-2285 ◽  
Author(s):  
Robert K. Flamm ◽  
Paul R. Rhomberg ◽  
Ronald N. Jones ◽  
David J. Farrell
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acinetobacter Baumannii ◽  
Active Agent ◽  
Multidrug Resistant ◽  
Surveillance Program ◽  
Gram Negative ◽  
Content Type ◽  
Highly Active ◽  
Bacterial Ribosome

ABSTRACTRX-P873 is a novel antibiotic from the pyrrolocytosine series which exhibits high binding affinity for the bacterial ribosome and broad-spectrum antibiotic properties. The pyrrolocytosines have shownin vitroactivity against multidrug-resistant Gram-negative and Gram-positive strains of bacteria known to cause complicated urinary tract, skin, and lung infections, as well as sepsis.Enterobacteriaceae(657),Pseudomonas aeruginosa(200), andAcinetobacter baumannii(202) isolates from North America and Europe collected in 2012 as part of a worldwide surveillance program were testedin vitroby broth microdilution using Clinical and Laboratory Standards Institute (CLSI) methodology. RX-P873 (MIC90, 0.5 μg/ml) was >32-fold more active than ceftazidime and inhibited 97.1% and 99.5% ofEnterobacteriaceaeisolates at MIC values of ≤1 and ≤4 μg/ml, respectively. There were only three isolates with an MIC value of >4 μg/ml (all were indole-positiveProtea). RX-P873 (MIC50/90, 2/4 μg/ml) was highly active againstPseudomonas aeruginosaisolates, including isolates which were nonsusceptible to ceftazidime or meropenem. RX-P873 was 2-fold less active againstP. aeruginosathan tobramycin (MIC90, 2 μg/ml; 91.0% susceptible) and colistin (MIC90, 2 μg/ml; 99.5% susceptible) and 2-fold more potent than amikacin (MIC90, 8 μg/ml; 93.5% susceptible) and meropenem (MIC90, 8 μg/ml; 76.0% susceptible). RX-P873, the most active agent againstAcinetobacter baumannii(MIC90, 1 μg/ml), was 2-fold more active than colistin (MIC90, 2 μg/ml; 97.0% susceptible) and 4-fold more active than tigecycline (MIC90, 4 μg/ml). This novel agent merits further exploration of its potential against multidrug-resistant Gram-negative bacteria.

scholarly journals Characterization of RelA in Acinetobacter baumannii

2020 ◽  
Vol 202 (12) ◽  
Author(s):  
María Pérez-Varela ◽  
Aimee R. P. Tierney ◽  
Ju-Sim Kim ◽  
Andrés Vázquez-Torres ◽  
Philip Rather
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Multidrug Resistant ◽  
Cell Physiology ◽  
Content Type ◽  
Content Model ◽  
Transposon Insertion ◽  
Downstream Effectors

ABSTRACT In response to nutrient depletion, the RelA and SpoT proteins generate the signaling molecule (p)ppGpp, which then controls a number of downstream effectors to modulate cell physiology. In Acinetobacter baumannii strain AB5075, a relA ortholog (ABUW_3302) was identified by a transposon insertion that conferred an unusual colony phenotype. An in-frame deletion in relA (ΔrelA) failed to produce detectable levels of ppGpp when amino acid starvation was induced with serine hydroxamate. The ΔrelA mutant was blocked from switching from the virulent opaque colony variant (VIR-O) to the avirulent translucent colony variant (AV-T), but the rate of AV-T to VIR-O switching was unchanged. In addition, the ΔrelA mutation resulted in a pronounced hypermotile phenotype on 0.35% agar plates. This hypermotility was dependent on the activation of a LysR regulator ABUW_1132, which was required for expression of AbaR, a LuxR family quorum-sensing regulator. In the ΔrelA mutant, ABUW_1132 was also required for the increased expression of an operon composed of the ABUW_3766-ABUW_3773 genes required for production of the surfactant-like lipopeptide acinetin 505. Additional phenotypes identified in the ΔrelA mutant included (i) cell elongation at high density, (ii) reduced formation of persister cells tolerant to colistin and rifampin, and (iii) decreased virulence in a Galleria mellonella model. IMPORTANCE Acinetobacter baumannii is a pathogen of worldwide importance. Due to the increasing prevalence of antibiotic resistance, these infections are becoming increasingly difficult to treat. New therapies are required to combat multidrug-resistant isolates. The role of RelA in A. baumannii is largely unknown. This study demonstrates that like in other bacteria, RelA controls a variety of functions, including virulence. Strategies to inhibit the activity of RelA and the resulting production of ppGpp could inhibit virulence and may represent a new therapeutic approach.

scholarly journals Efficacy of Apramycin against Multidrug-Resistant Acinetobacter baumannii in the Murine Neutropenic Thigh Model

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Anthony D. Kang ◽  
Kenneth P. Smith ◽  
Anders H. Berg ◽  
Katherine A. Truelson ◽  
George M. Eliopoulos ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Maximum Concentration ◽  
Area Under The Curve ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Model Treatment

ABSTRACT Apramycin, an aminocyclitol aminoglycoside, was rapidly bactericidal against Acinetobacter baumannii . In a neutropenic murine thigh infection model, treatment-associated A. baumannii CFU reductions of >4 log 10 per thigh were observed for all exposures for which area under the curve (AUC)/MIC ratio was >50 and maximum concentration of drug in serum ( C max )/MIC was ≈10 or higher. Based on these findings, we suggest that apramycin deserves further preclinical exploration as a repurposed therapeutic for multidrug-resistant Gram-negative pathogens, including A. baumannii .

scholarly journals Synergistic Activity of Colistin-Containing Combinations against Colistin-ResistantEnterobacteriaceae

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Thea Brennan-Krohn ◽  
Alejandro Pironti ◽  
James E. Kirby
Keyword(s):  
Treatment Options ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Resistant Strains ◽  
Bacterial Outer Membrane ◽  
Time Kill ◽  
Synergistic Combinations

ABSTRACTResistance to colistin, a polypeptide drug used as an agent of last resort for the treatment of infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, including carbapenem-resistantEnterobacteriaceae(CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistantEnterobacteriaceaeisolates, 15 of which were also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and the activities of those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the 4 most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in the checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative bacterial outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

scholarly journals Clinical Experience of Colistin-Glycopeptide Combination in Critically Ill Patients Infected with Gram-Negative Bacteria

2013 ◽  
Vol 58 (2) ◽  
pp. 851-858 ◽  
Author(s):  
Nicola Petrosillo ◽  
Maddalena Giannella ◽  
Massimo Antonelli ◽  
Mario Antonini ◽  
Bruno Barsic ◽  
...  
Keyword(s):  
Protective Factor ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Causative Agents ◽  
Treatment Onset ◽  
Cox Analysis

ABSTRACTA colistin-glycopeptide combination (CGC) has been shownin vitroto be synergistic against multidrug-resistant Gram-negative bacteria (MDR GNB), especiallyAcinetobacter baumannii, and to prevent further resistance. However, clinical data are lacking. We carried out a retrospective multicenter study of patients hospitalized in intensive care units (ICUs) who received colistin for GNB infection over a 1-year period, to assess the rates of nephrotoxicity and 30-day mortality after treatment onset among patients treated with and without CGC for ≥48 h. Of the 184 patients treated with colistin, GNB infection was documented for 166. The main causative agents were MDRA. baumannii(59.6%), MDRPseudomonas aeruginosa(18.7%), and carbapenem-resistantKlebsiella pneumoniae(14.5%); in 16.9% of patients, a Gram-positive bacterium (GPB) coinfection was documented. Overall, 68 patients (40.9%) received CGC. Comparison of patients treated with and without CGC showed significant differences for respiratory failure (39.7% versus 58.2%), ventilator-associated pneumonia (54.4% versus 71.4%), MDRA. baumanniiinfection (70.6% versus 52%), and GPB coinfection (41.2% versus 0%); there were no differences for nephrotoxicity (11.8% versus 13.3%) and 30-day mortality (33.8% versus 29.6%). Cox analysis performed on patients who survived for ≥5 days after treatment onset showed that the Charlson index (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.01 to 1.44;P= 0.001) and MDRA. baumanniiinfection (HR, 2.51; 95% CI, 1.23 to 5.12;P= 0.01) were independent predictors of 30-day mortality, whereas receiving CGC for ≥5 days was a protective factor (HR, 0.42; 95% CI, 0.19 to 0.93;P= 0.03). We found that CGC was not associated with higher nephrotoxicity and was a protective factor for mortality if administered for ≥5 days.

scholarly journals Novel Engineered Peptides of a Phage Lysin as Effective Antimicrobials against Multidrug-Resistant Acinetobacter baumannii

2016 ◽  
Vol 60 (5) ◽  
pp. 2671-2679 ◽  
Author(s):  
Mya Thandar ◽  
Rolf Lood ◽  
Benjamin Y. Winer ◽  
Douglas R. Deutsch ◽  
Chad W. Euler ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Bacterial Pathogen ◽  
Antibacterial Activities ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Content Type ◽  
Human Red Blood Cells ◽  
Phage Lysin

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug-resistantA. baumanniiclones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the present study, we show that the C-terminal amino acids 108 to 138 of phage lysin PlyF307, named P307, alone were sufficient to killA. baumannii(>3 logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C(>5-log kill). Both P307 and P307SQ-8Cshowed highin vitroactivity againstA. baumanniiin biofilms. Moreover, P307SQ-8Cexhibited MICs comparable to those of levofloxacin and ceftazidime and acted synergistically with polymyxin B. Although the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model ofA. baumanniiskin infection, P307SQ-8Creduced the bacterial burden by ∼2 logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

scholarly journals Deciphering Multidrug-Resistant Acinetobacter baumannii from a Pediatric Cancer Hospital in Egypt

mSphere ◽  
2021 ◽  
Author(s):  
Deena Jalal ◽  
Mariam G. Elzayat ◽  
Aya A. Diab ◽  
Hend E. El-Shqanqery ◽  
Omar Samir ◽  
...  
Keyword(s):  
Antimicrobial Agent ◽  
Acinetobacter Baumannii ◽  
Cancer Patients ◽  
Pediatric Cancer ◽  
Mortality Rates ◽  
Multidrug Resistant ◽  
Major Health ◽  
Content Type ◽  
Development Of Resistance ◽  
Carbapenem Resistant

Acinetobacter baumannii represents a major health threat, in particular among immunocompromised cancer patients. The rise in carbapenem-resistant A. baumannii , and the development of resistance to the last-resort antimicrobial agent colistin, complicates the management of A. baumannii outbreaks and increases mortality rates.

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