scholarly journals In VitroandIn VivoAntimicrobial Activities of Gallium Nitrate against Multidrug-Resistant Acinetobacter baumannii

2012 ◽  
Vol 56 (11) ◽  
pp. 5961-5970 ◽  
Author(s):  
Luísa C. S. Antunes ◽  
Francesco Imperi ◽  
Fabrizia Minandri ◽  
Paolo Visca
Keyword(s):  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Therapeutic Potential ◽  
Survival Rates ◽  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Gallium Nitrate ◽  
Content Type ◽  
Bacterial Physiology

ABSTRACTMultidrug-resistantAcinetobacter baumanniiposes a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumanniichemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO3)3, the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58A. baumanniistrains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO3)3delayed the entry ofA. baumanniiinto the exponential phase and drastically reduced bacterial growth rates. Ga(NO3)3activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO3)3also protectedGalleria mellonellalarvae from lethalA. baumanniiinfection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO3)3inhibited the growth in human serum of 76% of the multidrug-resistantA. baumanniiisolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment ofA. baumanniibloodstream infections. Ga(NO3)3also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistantA. baumannii.

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 Pyoverdine and Proteases Affect the Response of Pseudomonas aeruginosa to Gallium in Human Serum

2015 ◽  
Vol 59 (9) ◽  
pp. 5641-5646 ◽  
Author(s):  
Carlo Bonchi ◽  
Emanuela Frangipani ◽  
Francesco Imperi ◽  
Paolo Visca
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Human Serum ◽  
Bloodstream Infections ◽  
Proteinase K ◽  
Gallium Nitrate ◽  
Iron Availability ◽  
Content Type ◽  
Iron Restriction ◽  
Casamino Acids

ABSTRACTGallium is an iron mimetic which has recently been repurposed as an antibacterial agent due to its capability to disrupt bacterial iron metabolism. In this study, the antibacterial activity of gallium nitrate [Ga(NO3)3] was investigated in complement-free human serum (HS) on 55Pseudomonas aeruginosaclinical isolates from cystic fibrosis and non-cystic fibrosis patients. The susceptibility ofP. aeruginosato Ga(NO3)3in HS was dependent on the bacterial ability to acquire iron from serum binding proteins (i.e., transferrin). The extent of serum protein degradation correlated well withP. aeruginosagrowth in HS, while pyoverdine production did not. However, pyoverdine-deficientP. aeruginosastrains were unable to grow in HS and overcome iron restriction, albeit capable of releasing proteases. Predigestion of HS with proteinase K promoted the growth of all strains, irrespective of their ability to produce proteases and/or pyoverdine. The MICs of Ga(NO3)3were higher in HS than in an iron-poor Casamino Acids medium, where proteolysis does not affect iron availability. Coherently, strains displaying high proteolytic activity were less susceptible to Ga(NO3)3in HS. Our data support a model in which both pyoverdine and proteases affect the response ofP. aeruginosato Ga(NO3)3in HS. The relatively high Ga(NO3)3concentration required to inhibit the growth of highly proteolyticP. aeruginosaisolates in HS poses a limitation to the potential of Ga(NO3)3in the treatment ofP. aeruginosabloodstream infections.

scholarly journals In VitroandIn VivoBiological Activities of Iron Chelators and Gallium Nitrate against Acinetobacter baumannii

2012 ◽  
Vol 56 (10) ◽  
pp. 5397-5400 ◽  
Author(s):  
Louis de Léséleuc ◽  
Greg Harris ◽  
Rhonda KuoLee ◽  
Wangxue Chen
Keyword(s):  
Acinetobacter Baumannii ◽  
Iron Metabolism ◽  
Multidrug Resistant ◽  
Iron Chelators ◽  
Gallium Nitrate ◽  
Content Type ◽  
Iron Restriction ◽  
Nitrate Treatment

ABSTRACTWe investigated the ability of compounds interfering with iron metabolism to inhibit the growth ofAcinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibitedA. baumanniigrowthin vitro. Gallium nitrate alone was moderately effective at reducingA. baumanniigrowth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistantA. baumannii.

scholarly journals Severe Acinetobacter baumannii Sepsis Is Associated with Elevation of Pentraxin 3

2014 ◽  
Vol 82 (9) ◽  
pp. 3910-3918 ◽  
Author(s):  
Patrick M. Ketter ◽  
M. Neal Guentzel ◽  
Beverly Schaffer ◽  
Maryanne Herzig ◽  
Xiaowu Wu ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Lethal Dose ◽  
Antimicrobial Properties ◽  
Bloodstream Infections ◽  
Multidrug Resistant ◽  
Mouse Serum ◽  
Myeloperoxidase Activity ◽  
Content Type

ABSTRACTMultidrug-resistantAcinetobacter baumanniiis among the most prevalent bacterial pathogens associated with trauma-related wound and bloodstream infections. Although septic shock and disseminated intravascular coagulation have been reported following fulminantA. baumanniisepsis, little is known about the protective host immune response to this pathogen. In this study, we examined the role of PTX3, a soluble pattern recognition receptor with reported antimicrobial properties and stored within neutrophil granules. PTX3 production by murine J774a.1 macrophages was assessed following challenge withA. baumanniistrains ATCC 19606 and clinical isolates (CI) 77, 78, 79, 80, and 86. Interestingly, only CI strains 79, 80, and 86 induced PTX3 synthesis in murine J774a.1 macrophages, with greatest production observed following CI 79 and 86 challenge. Subsequently, C57BL/6 mice were challenged intraperitoneally with CI 77 and 79 to assess the role of PTX3in vivo.A. baumanniistrain CI 79 exhibited significantly (P< 0.0005) increased mortality, with an approximate 50% lethal dose (LD50) of 105CFU, while an equivalent dose of CI 77 exhibited no mortality. Plasma leukocyte chemokines (KC, MCP-1, and RANTES) and myeloperoxidase activity were also significantly elevated following challenge with CI 79, indicating neutrophil recruitment/activation associated with significant elevation in serum PTX3 levels. Furthermore, 10-fold-greater PTX3 levels were observed in mouse serum 12 h postchallenge, comparing CI 79 to CI 77 (1,561 ng/ml versus 145 ng/ml), with concomitant severe pathology (liver and spleen) and coagulopathy. Together, these results suggest that elevation of PTX3 is associated with fulminant disease duringA. baumanniisepsis.

scholarly journals In VivoEfficacy of Glycopeptide-Colistin Combination Therapies in aGalleria mellonellaModel ofAcinetobacter baumanniiInfection

2011 ◽  
Vol 55 (7) ◽  
pp. 3534-3537 ◽  
Author(s):  
M. Hornsey ◽  
D. W. Wareham
Keyword(s):  
Galleria Mellonella ◽  
Survival Rates ◽  
Multidrug Resistant ◽  
New Agents ◽  
Content Type ◽  
Highly Active ◽  
Resistant Strains ◽  
Immunomodulatory Action ◽  
Lethal Doses

ABSTRACTThe treatment ofAcinetobacter baumanniiinfections poses a significant clinical challenge, with isolates resistant to all commonly used agents increasingly being reported. With few new agents in the pipeline, clinicians are increasingly turning to combinations of antimicrobials in the hope that they may act synergistically together. In this study we assessed the activities of two glycopeptide-colistin combinations bothin vitroand using aGalleria mellonellacaterpillar model ofA. baumanniiinfection. In checkerboard assays both vancomycin and teicoplanin were highly active against susceptible and multidrug-resistant strains ofA. baumanniiwhen combined with colistin (fractional inhibitory concentration [FIC] of <0.25). Treatment ofG. mellonellacaterpillars infected with lethal doses ofA. baumanniiresulted in significantly enhanced survival rates when either vancomycin or teicoplanin was given with colistin compared to colistin treatment alone (P< 0.05). This effect was most marked when vancomycin was the glycopeptide administered, although this agent was also highly effective as monotherapy, possibly through an immunomodulatory action on theG. mellonellaresponse toA. baumanniiinfection. This work suggests that glycopeptide-colistin combinations are highly active againstA. baumanniibothin vitroand in a simple animal model of infection. They should be considered further as potential treatments for difficult-to-treatA. baumanniiinfections.

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 CsrA Supports both Environmental Persistence and Host-Associated Growth of Acinetobacter baumannii

2020 ◽  
Vol 88 (12) ◽  
Author(s):  
John M. Farrow ◽  
Greg Wells ◽  
Samantha Palethorpe ◽  
Mark D. Adams ◽  
Everett C. Pesci
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Growth Defect ◽  
Gene Encoding ◽  
Content Type ◽  
Indirect Transmission ◽  
Mutant Strains ◽  
Carbon Storage Regulator

ABSTRACT Acinetobacter baumannii is an opportunistic and frequently multidrug-resistant Gram-negative bacterial pathogen that primarily infects critically ill individuals. Indirect transmission from patient to patient in hospitals can drive infections, supported by this organism’s abilities to persist on dry surfaces and rapidly colonize susceptible individuals. To investigate how A. baumannii survives on surfaces, we cultured A. baumannii in liquid media for several days and then analyzed isolates that lost the ability to survive drying. One of these isolates carried a mutation that affected the gene encoding the carbon storage regulator CsrA. As we began to examine the role of CsrA in A. baumannii, we observed that the growth of ΔcsrA mutant strains was inhibited in the presence of amino acids. The ΔcsrA mutant strains had a reduced ability to survive drying and to form biofilms but an improved ability to tolerate increased osmolarity compared with the wild type. We also examined the importance of CsrA for A. baumannii virulence. The ΔcsrA mutant strains had a greatly reduced ability to kill Galleria mellonella larvae, could not replicate in G. mellonella hemolymph, and also had a growth defect in human serum. Together, these results show that CsrA is essential for the growth of A. baumannii on host-derived substrates and is involved in desiccation tolerance, implying that CsrA controls key functions involved in the transmission of A. baumannii in hospitals.

scholarly journals Antimicrobial Activity of Gallium Protoporphyrin IX against Acinetobacter baumannii Strains Displaying Different Antibiotic Resistance Phenotypes

2015 ◽  
Vol 59 (12) ◽  
pp. 7657-7665 ◽  
Author(s):  
Brock A. Arivett ◽  
Steven E. Fiester ◽  
Emily J. Ohneck ◽  
William F. Penwell ◽  
Cynthia M. Kaufman ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
Protoporphyrin Ix ◽  
Multidrug Resistant ◽  
Content Type ◽  
Antibiotic Development ◽  
Alveolar Epithelial ◽  
Mueller Hinton ◽  
Novel Therapeutic Strategies

ABSTRACTA paucity of effective, currently available antibiotics and a lull in antibiotic development pose significant challenges for treatment of patients with multidrug-resistant (MDR)Acinetobacter baumanniiinfections. Thus, novel therapeutic strategies must be evaluated to meet the demands of treatment of these often life-threatening infections. Accordingly, we examined the antibiotic activity of gallium protoporphyrin IX (Ga-PPIX) against a collection ofA. baumanniistrains, including nonmilitary and military strains and strains representing different clonal lineages and isolates classified as susceptible or MDR. Susceptibility testing demonstrated that Ga-PPIX inhibits the growth of all tested strains when cultured in cation-adjusted Mueller-Hinton broth, with a MIC of 20 μg/ml. This concentration significantly reduced bacterial viability, while 40 μg/ml killed all cells of theA. baumanniiATCC 19606Tand ACICU MDR isolate after 24-h incubation. Recovery of ATCC 19606Tand ACICU strains from infected A549 human alveolar epithelial monolayers was also decreased when the medium was supplemented with Ga-PPIX, particularly at a 40-μg/ml concentration. Similarly, the coinjection of bacteria with Ga-PPIX increased the survival ofGalleria mellonellalarvae infected with ATCC 19606Tor ACICU. Ga-PPIX was cytotoxic only when monolayers or larvae were exposed to concentrations 16-fold and 1,250-fold higher than those showing antibacterial activity, respectively. These results indicate that Ga-PPIX could be a viable therapeutic option for treatment of recalcitrantA. baumanniiinfections regardless of the resistance phenotype, clone lineage, time and site of isolation of strains causing these infections and their iron uptake phenotypes or the iron content of the media.

scholarly journals Acinetobacter baumannii Biofilm Formation in Human Serum and Disruption by Gallium

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Federica Runci ◽  
Carlo Bonchi ◽  
Emanuela Frangipani ◽  
Daniela Visaggio ◽  
Paolo Visca
Keyword(s):  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Antibiotic Treatment ◽  
Biofilm Formation ◽  
Gallium Nitrate ◽  
Content Type ◽  
The Way

ABSTRACT Biofilm-associated infections caused by Acinetobacter baumannii are extremely recalcitrant to antibiotic treatment. We report that A. baumannii develops a mature biofilm when grown in complement-free human serum (HS). We demonstrate that 16 μM gallium nitrate (GaN) drastically reduces A. baumannii growth and biofilm formation in HS, whereas 64 μM GaN causes massive disruption of preformed A. baumannii biofilm. These findings pave the way to the repurposing of GaN as an antibiofilm agent for A. baumannii.

scholarly journals Personalized Therapeutic Cocktail of Wild Environmental Phages Rescues Mice from Acinetobacter baumannii Wound Infections

2016 ◽  
Vol 60 (10) ◽  
pp. 5806-5816 ◽  
Author(s):  
James M. Regeimbal ◽  
Anna C. Jacobs ◽  
Brendan W. Corey ◽  
Matthew S. Henry ◽  
Mitchell G. Thompson ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Galleria Mellonella ◽  
Therapeutic Option ◽  
Multidrug Resistant ◽  
Surrounding Tissue ◽  
Content Type ◽  
Wound Model ◽  
Spread Of Infection ◽  
Selection Event

ABSTRACTMultidrug-resistant bacterial pathogens are an increasing threat to public health, and lytic bacteriophages have reemerged as a potential therapeutic option. In this work, we isolated and assembled a five-member cocktail of wild phages againstAcinetobacter baumanniiand demonstrated therapeutic efficacy in a mouse full-thickness dorsal infected wound model. The cocktail lowers the bioburden in the wound, prevents the spread of infection and necrosis to surrounding tissue, and decreases infection-associated morbidity. Interestingly, this effective cocktail is composed of four phages that do not kill the parent strain of the infection and one phage that simply delays bacterial growthin vitrovia a strong but incomplete selection event. The cocktail here appears to function in a combinatorial manner, as one constituent phage targets capsulatedA. baumanniibacteria and selects for loss of receptor, shifting the population to an uncapsulated state that is then sensitized to the remaining four phages in the cocktail. Additionally, capsule is a known virulence factor forA. baumannii, and we demonstrated that the emergent uncapsulated bacteria are avirulent in aGalleria mellonellamodel. These results highlight the importance of anticipating population changes during phage therapy and designing intelligent cocktails to control emergent strains, as well as the benefits of using phages that target virulence factors. Because of the efficacy of this cocktail isolated from a limited environmental pool, we have established a pipeline for developing new phage therapeutics against additional clinically relevant multidrug-resistant pathogens by using environmental phages sourced from around the globe.

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