In-Depth Analysis of the Role of the Acinetobactin Cluster in the Virulence of Acinetobacter baumannii

Acinetobacter baumannii is a multidrug-resistant pathogen that represents a serious threat to global health. A. baumannii possesses a wide range of virulence factors that contribute to the bacterial pathogenicity. Among them, the siderophore acinetobactin is one of the most important, being essential for the development of the infection. In this study we performed an in-depth analysis of the acinetobactin cluster in the strain A. baumannii ATCC 17978. For this purpose, nineteen individual isogenic mutant strains were generated, and further phenotypical analysis were performed. Individual mutants lacking the biosynthetic genes entA, basG, basC, basD, and basB showed a significant loss in virulence, due to the disruption in the acinetobactin production. Similarly, the gene bauA, coding for the acinetobactin receptor, was also found to be crucial for the bacterial pathogenesis. In addition, the analysis of the ΔbasJ/ΔfbsB double mutant strain demonstrated the high level of genetic redundancy between siderophores where the role of specific genes of the acinetobactin cluster can be fulfilled by their fimsbactin redundant genes. Overall, this study highlights the essential role of entA, basG, basC, basD, basB and bauA in the pathogenicity of A. baumannii and provides potential therapeutic targets for the design of new antivirulence agents against this microorganism.

Download Full-text

Molecular survey of mcr1 and mcr2 plasmid mediated colistin resistance genes in Escherichia coli isolates of animal origin in Iran

BMC Research Notes ◽

10.1186/s13104-021-05519-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kayhan Ilbeigi ◽

Mahdi Askari Badouei ◽

Hossein Vaezi ◽

Hassan Zaheri ◽

Sina Aghasharif ◽

...

Keyword(s):

Escherichia Coli ◽

Resistance Genes ◽

Companion Animals ◽

Multidrug Resistant ◽

Animal Origin ◽

Colistin Resistance ◽

E Coli ◽

High Level ◽

Farming Industry

Abstract Objectives The emergence of colistin-resistant Enterobacteriaceae from human and animal sources is one of the major public health concerns as colistin is the last-resort antibiotic for treating infections caused by multidrug-resistant Gram-negative bacteria. We aimed to determine the prevalence of the prototype widespread colistin resistance genes (mcr-1 and mcr-2) among commensal and pathogenic Escherichia coli strains isolated from food-producing and companion animals in Iran. Results A total of 607 E. coli isolates which were previously collected from different animal sources between 2008 and 2016 used to uncover the possible presence of plasmid-mediated colistin resistance genes (mcr-1 and mcr-2) by PCR. Overall, our results could not confirm the presence of any mcr-1 or mcr-2 positive E. coli among the studied isolates. It is concluded that despite the important role of food-producing animals in transferring the antibiotic resistance, they were not the main source for carriage of mcr-1 and mcr-2 in Iran until 2016. This study suggests that the other mcr variants (mcr-3 to mcr-9) might be responsible for conferring colistin resistance in animal isolates in Iran. The possible linkage between pig farming industry and high level of mcr carriage in some countries needs to be clarified in future prospective studies.

Download Full-text

Structure and function relationships of proteins based on polar profile: a review.

Acta Biochimica Polonica ◽

10.18388/abp.2014_919 ◽

2016 ◽

Vol 63 (2) ◽

Cited By ~ 4

Author(s):

Carlos Polanco ◽

Thomas Buhse ◽

Vladimir N Uversky

Keyword(s):

Mathematical Structure ◽

Quantitative Structure Activity Relationship ◽

Multidrug Resistant ◽

Training Data ◽

Main Function ◽

Pharmaceutical Drugs ◽

Linear Sequence ◽

Wide Range ◽

High Level ◽

And Function

Proteins in the post-genome era impose diverse research challenges, the main are the understanding of their structure-function mechanism, and the growing need for new pharmaceutical drugs, particularly antibiotics that help clinicians treat the ever- increasing number of Multidrug-Resistant Organisms (MDROs). Although, there is a wide range of mathematical-computational algorithms to satisfy the demand, among them the Quantitative Structure-Activity Relationship algorithms that have shown better performance using a characteristic training data of the property searched; their performance has stagnated regardless of the number of metrics they evaluate and their complexity. This article reviews the characteristics of these metrics, and the need to reconsider the mathematical structure that expresses them, directing their design to a more comprehensive algebraic structure. It also shows how the main function of a protein can be determined by measuring the polarity of its linear sequence, with a high level of accuracy, and how such exhaustive metric stands as a "fingerprint" that can be applied to scan the protein regions to obtain new pharmaceutical drugs, and thus to establish how the singularities led to the specialization of the protein groups known today.

Download Full-text

Colistin heteroresistance and the involvement of the PmrAB regulatory system in Acinetobacter baumannii

10.1101/307132 ◽

2018 ◽

Author(s):

Yannick Charretier ◽

Seydina M. Diene ◽

Damien Baud ◽

Sonia Chatellier ◽

Emmanuelle Santiago-Allexant ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Population Analysis ◽

Regulatory System ◽

Clinical Problem ◽

Multidrug Resistant ◽

Regulatory Pathway ◽

Colistin Resistance ◽

Bacterial Killing ◽

One Step

AbstractMultidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used as last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance to colistin have been described. Mutations in the PmrAB regulatory pathway have been already associated with colistin resistance whereas the mechanisms for heteroresistance remain largely unknown. The purpose of the present study is to investigate the role of PmrAB in laboratory-selected mutants representative of global epidemic strains. During brief colistin exposure, colistin resistant and colistin heteroresistant mutants were selected in a one-step strategy. Population Analysis Profiling (PAP) was performed to confirm the suspected phenotype. Upon withdrawal of selective pressure, compensatory mutations were evaluated in another one-step strategy. A trans-complementation assay was designed to delineate the involvement of the PmrAB regulatory system using qPCR and PAP. Mutations in the PmrAB regulatory pathway were associated with colistin resistance and colistin heteroresistance as well. The transcomplementation assay provides a proof for the role played by changes in the PmrAB regulatory pathway. The level of colistin resistance is correlated to the level of expression of pmrC. The resistance phenotype was partially restored since the complemented strain became heteroresistant. This report shows the role of different mutations in the PmrAB regulatory pathway and warns on the development of colistin heteroresistance that could be present but not easily detected with routine testing.

Download Full-text

Characterization of RelA in Acinetobacter baumannii

Journal of Bacteriology ◽

10.1128/jb.00045-20 ◽

2020 ◽

Vol 202 (12) ◽

Cited By ~ 3

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.

Download Full-text

The Role of the CopA Copper Efflux System in Acinetobacter baumannii Virulence

International Journal of Molecular Sciences ◽

10.3390/ijms20030575 ◽

2019 ◽

Vol 20 (3) ◽

pp. 575 ◽

Cited By ~ 11

Author(s):

Saleh Alquethamy ◽

Marjan Khorvash ◽

Victoria Pederick ◽

Jonathan Whittall ◽

James Paton ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Copper Toxicity ◽

In Silico Analysis ◽

Opportunistic Pathogen ◽

Copper Resistance ◽

Copper Stress ◽

Causative Agents ◽

High Level ◽

P Type

Acinetobacter baumannii has emerged as one of the leading causative agents of nosocomial infections. Due to its high level of intrinsic and adapted antibiotic resistance, treatment failure rates are high, which allows this opportunistic pathogen to thrive during infection in immune-compromised patients. A. baumannii can cause infections within a broad range of host niches, with pneumonia and bacteraemia being associated with the greatest levels of morbidity and mortality. Although its resistance to antibiotics is widely studied, our understanding of the mechanisms required for dealing with environmental stresses related to virulence and hospital persistence, such as copper toxicity, is limited. Here, we performed an in silico analysis of the A. baumannii copper resistome, examining its regulation under copper stress. Using comparative analyses of bacterial P-type ATPases, we propose that A. baumannii encodes a member of a novel subgroup of P1B-1 ATPases. Analyses of three putative inner membrane copper efflux systems identified the P1B-1 ATPase CopA as the primary mediator of cytoplasmic copper resistance in A. baumannii. Using a murine model of A. baumannii pneumonia, we reveal that CopA contributes to the virulence of A. baumannii. Collectively, this study advances our understanding of how A. baumannii deals with environmental copper toxicity, and it provides novel insights into how A. baumannii combats adversities encountered as part of the host immune defence.

Download Full-text

Possible role of integrase gene polymerase chain reaction as an epidemiological marker: study of multidrug-resistant Acinetobacter baumannii isolated from nosocomial infections

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2006.11.014 ◽

2007 ◽

Vol 29 (4) ◽

pp. 446-450 ◽

Cited By ~ 11

Author(s):

Abhishek Gaur ◽

Pradyot Prakash ◽

Shampa Anupurba ◽

Tribhuban M. Mohapatra

Keyword(s):

Polymerase Chain Reaction ◽

Acinetobacter Baumannii ◽

Nosocomial Infections ◽

Multidrug Resistant ◽

Chain Reaction ◽

Integrase Gene ◽

Gene Polymerase Chain Reaction ◽

Marker Study ◽

Polymerase Chain

Download Full-text

Genetic Basis of Multidrug Resistance in Acinetobacter baumannii Clinical Isolates at a Tertiary Medical Center in Pennsylvania

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00570-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 3837-3843 ◽

Cited By ~ 95

Author(s):

Jennifer M. Adams-Haduch ◽

David L. Paterson ◽

Hanna E. Sidjabat ◽

Anthony W. Pasculle ◽

Brian A. Potoski ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Genetic Basis ◽

Medical Center ◽

Multidrug Resistant ◽

Quinolone Resistance ◽

Clinical Isolates ◽

Clinical Microbiology Laboratory ◽

Carbapenemase Gene ◽

Methylase Gene ◽

High Level

ABSTRACT A total of 49 unique clinical isolates of multidrug-resistant (MDR) Acinetobacter baumannii identified at a tertiary medical center in Pittsburgh, Pennsylvania, between August 2006 and September 2007 were studied for the genetic basis of their MDR phenotype. Approximately half of all A. baumannii clinical isolates identified during this period qualified as MDR, defined by nonsusceptibility to three or more of the antimicrobials routinely tested in the clinical microbiology laboratory. Among the MDR isolates, 18.4% were resistant to imipenem. The frequencies of resistance to amikacin and ciprofloxacin were high at 36.7% and 95.9%, respectively. None of the isolates was resistant to colistin or tigecycline. The presence of the carbapenemase gene bla OXA-23 and the 16S rRNA methylase gene armA predicted high-level resistance to imipenem and amikacin, respectively. bla OXA-23 was preceded by insertion sequence ISAba1, which likely provided a potent promoter activity for the expression of the carbapenemase gene. The structure of the transposon defined by ISAba1 differed from those reported in Europe, suggesting that ISAba1-mediated acquisition of bla OXA-23 may occur as an independent event. Typical substitutions in the quinolone resistance-determining regions of the gyrA and parC genes were observed in the ciprofloxacin-resistant isolates. Plasmid-mediated quinolone resistance genes, including the qnr genes, were not identified. Fifty-nine percent of the MDR isolates belonged to a single clonal group over the course of the study period, as demonstrated by pulsed-field gel electrophoresis.

Download Full-text

Extended-Spectrum Cephalosporinase in Acinetobacter baumannii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00050-10 ◽

2010 ◽

Vol 54 (8) ◽

pp. 3484-3488 ◽

Cited By ~ 46

Author(s):

José-Manuel Rodríguez-Martínez ◽

Patrice Nordmann ◽

Esthel Ronco ◽

Laurent Poirel

Keyword(s):

Acinetobacter Baumannii ◽

Clinical Isolate ◽

Site Directed Mutagenesis ◽

Directed Mutagenesis ◽

Extended Spectrum ◽

Class C ◽

High Level ◽

Level Resistance

ABSTRACT An AmpC-type β-lactamase conferring high-level resistance to expanded-spectrum cephalosporins and monobactams was characterized from an Acinetobacter baumannii clinical isolate. This class C β-lactamase (named ADC-33) possessed a Pro210Arg substitution together with a duplication of an Ala residue at position 215 (inside the Ω-loop) compared to a reference AmpC cephalosporinase from A. baumannii. ADC-33 hydrolyzed ceftazidime, cefepime, and aztreonam at high levels, which allows the classification of this enzyme as an extended-spectrum AmpC (ESAC). Site-directed mutagenesis confirmed the role of both substitutions in its ESAC property.

Download Full-text

Foresight as a tool of public administration in the field of science, technology and innovation

Economics Entrepreneurship Management ◽

10.23939/eem2021.01.090 ◽

2021 ◽

Vol 8 (1) ◽

pp. 90-97

Author(s):

T. Kvasha ◽

◽

L. Musina ◽

Keyword(s):

New Technologies ◽

National Level ◽

Research And Innovation ◽

Science Technology ◽

Wide Range ◽

Smart Specialization ◽

High Level ◽

First Time ◽

Science Technology And Innovation

Given the growing role of technological foresight as a tool for reconciling visions, goals and ways of STI development in an era of rapid technological change and global challenges, the approach to foresight research to select priorities for science and innovation in Ukraine for 2022–2026 has been improved. It takes into account a wide range of national targets for achieving SDGs by 2030. The developed Methodological recommendations provided a thorough analysis of more than 3,000 potentially acceptable technological and innovative proposals. The approach to setting STI priorities is new for Ukraine and involves a consistent process of selecting the top 30 most acceptable proposals in each of the seven thematic areas through five stages of discussions and evaluations. The result was the formation of a database of technology passports and developments on the experts’ proposals, their selection by practitioners, ranking, evaluation in terms of the potential of Ukrainian science and relevance in terms of world science and new technologies using international databases. They are the basis for decisions by the Expert Councils and the High-Level Working Group on key thematic areas and the preparation of a relevant draft government decision. Despite the conditions of quarantine, for the first time more than 2,500 experts from science, business, state and public organizations took part in the discussions, which is the basis for impartial and public decision-making. To strengthen the role of foresight as a tool for public planning and management in the field of STI, it is proposed to develop a STI roadmap as part of a research and innovation strategy for smart specialization (RIS 3) at the national level.

Download Full-text