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

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.

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

mSphere ◽

10.1128/msphere.00793-20 ◽

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.

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1480 ◽

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)

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Erratum to: Education: The role of the first siderophore cephalosporin Fetcroja® (cefiderocol) in UK clinical practice: introduction; Education: An introduction to the core data for cefiderocol with reflections for a possible role within UK clinical practice; Education: A compassionate use of cefiderocol to treat osteomyelitis caused by an XDR Pseudomonas aeruginosa; Compassionate use of cefiderocol for carbapenem-resistant Acinetobacter baumannii prosthetic joint infection; Education: An overview from the author of ‘Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in intensive care unit patients’

JAC-Antimicrobial Resistance ◽

10.1093/jacamr/dlab110 ◽

2021 ◽

Vol 3 (3) ◽

Keyword(s):

Clinical Practice ◽

Acinetobacter Baumannii ◽

Rescue Therapy ◽

Joint Infection ◽

Compassionate Use ◽

Gram Negative ◽

The Core ◽

Carbapenem Resistant ◽

Prosthetic Joint

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Erratum to: Education: The role of the first siderophore cephalosporin Fetcroja® (cefiderocol) in UK clinical practice: introduction; Antibiotic resistance during and beyond COVID-19; Education: An introduction to the core data for cefiderocol with reflections for a possible role within UK clinical practice; Education: A compassionate use of cefiderocol to treat osteomyelitis caused by an XDR Pseudomonas aeruginosa; Compassionate use of cefiderocol for carbapenem-resistant Acinetobacter baumannii prosthetic joint infection; Education: An overview from the author of ‘Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in intensive care unit patients’

JAC-Antimicrobial Resistance ◽

10.1093/jacamr/dlab109 ◽

2021 ◽

Vol 3 (3) ◽

Keyword(s):

Clinical Practice ◽

Acinetobacter Baumannii ◽

Rescue Therapy ◽

Joint Infection ◽

Compassionate Use ◽

Gram Negative ◽

The Core ◽

Carbapenem Resistant ◽

Prosthetic Joint

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01221-20 ◽

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.

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An Evidence-Based Multidisciplinary Approach Focused on Creating Algorithms for Targeted Therapy of Infection-Related Ventilator-Associated Complications (IVACs) Caused by Pseudomonas aeruginosa and Acinetobacter baumannii in Critically Ill Adult Patients

Antibiotics ◽

10.3390/antibiotics11010033 ◽

2021 ◽

Vol 11 (1) ◽

pp. 33

Author(s):

Milo Gatti ◽

Bruno Viaggi ◽

Gian Maria Rossolini ◽

Federico Pea ◽

Pierluigi Viale

Keyword(s):

Pseudomonas Aeruginosa ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Fourth Generation ◽

Evidence Based ◽

Beta Lactamase ◽

Beta Lactam ◽

Gram Negative ◽

Carbapenem Resistant ◽

Therapeutic Choice

(1) Background: To develop evidence-based algorithms for targeted antibiotic therapy of infection-related ventilator-associated complications (IVACs) caused by non-fermenting Gram-negative pathogens. (2) Methods: A multidisciplinary team of four experts had several rounds of assessments for developing algorithms devoted to targeted antimicrobial therapy of IVACs caused by two non-fermenting Gram-negative pathogens. A literature search was performed on PubMed-MEDLINE (until September 2021) to provide evidence for supporting therapeutic choices. Quality and strength of evidence was established according to a hierarchical scale of the study design. Six different algorithms with associated recommendations in terms of therapeutic choice and dosing optimization were suggested according to the susceptibility pattern of two non-fermenting Gram-negative pathogens: multi-susceptible Pseudomonas aeruginosa (PA), multidrug-resistant (MDR) metallo-beta-lactamase (MBL)-negative-PA, MBL-positive-PA, carbapenem-susceptible Acinetobacter baumannii (AB), and carbapenem-resistant AB. (3) Results: Piperacillin–tazobactam or fourth-generation cephalosporins represent the first therapeutic choice in IVACs caused by multi-susceptible PA. A carbapenem-sparing approach favouring the administration of novel beta-lactam/beta-lactamase inhibitors should be pursued in the management of MDR-MBL-negative PA infections. Cefiderocol should be used as first-line therapy for the management of IVACs caused by MBL-producing-PA or carbapenem-resistant AB. Fosfomycin-based combination therapy, as well as inhaled colistin, could be considered as a reasonable alternative for the management of IVACs due to MDR-PA and carbapenem-resistant AB. (4) Conclusions: The implementation of algorithms focused on prompt revision of antibiotic regimens guided by results of conventional and rapid diagnostic methodologies, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens is strongly suggested.

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Role of the Gram-Negative Envelope Stress Response in the Presence of Antimicrobial Agents

Trends in Microbiology ◽

10.1016/j.tim.2016.03.001 ◽

2016 ◽

Vol 24 (5) ◽

pp. 377-390 ◽

Cited By ~ 36

Author(s):

Randi L. Guest ◽

Tracy L. Raivio

Keyword(s):

Stress Response ◽

Antimicrobial Agents ◽

Gram Negative ◽

Envelope Stress

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Histone-like nucleoid-structuring protein (H-NS) regulatory role in antibiotic resistance in Acinetobacter baumannii

Scientific Reports ◽

10.1038/s41598-021-98101-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Deja Rodgers ◽

Casin Le ◽

Camila Pimentel ◽

Marisel R. Tuttobene ◽

Tomás Subils ◽

...

Keyword(s):

Antibiotic Resistance ◽

Stress Response ◽

Antimicrobial Resistance ◽

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Network Control ◽

Regulatory Role ◽

Transcriptional Level ◽

Expression Of Genes

AbstractIn the multidrug resistant (MDR) pathogen Acinetobacter baumannii the global repressor H-NS was shown to modulate the expression of genes involved in pathogenesis and stress response. In addition, H-NS inactivation results in an increased resistance to colistin, and in a hypermotile phenotype an altered stress response. To further contribute to the knowledge of this key transcriptional regulator in A. baumannii behavior, we studied the role of H-NS in antimicrobial resistance. Using two well characterized A. baumannii model strains with distinctive resistance profile and pathogenicity traits (AB5075 and A118), complementary transcriptomic and phenotypic approaches were used to study the role of H-NS in antimicrobial resistance, biofilm and quorum sensing gene expression. An increased expression of genes associated with β-lactam resistance, aminoglycosides, quinolones, chloramphenicol, trimethoprim and sulfonamides resistance in the Δhns mutant background was observed. Genes codifying for efflux pumps were also up-regulated, with the exception of adeFGH. The wild-type transcriptional level was restored in the complemented strain. In addition, the expression of biofilm related genes and biofilm production was lowered when the transcriptional repressor was absent. The quorum network genes aidA, abaI, kar and fadD were up-regulated in Δhns mutant strains. Overall, our results showed the complexity and scope of the regulatory network control by H-NS (genes involved in antibiotic resistance and persistence). These observations brings us one step closer to understanding the regulatory role of hns to combat A. baumannii infections.

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