scholarly journals The Acinetobacter baumannii Znu System Overcomes Host-Imposed Nutrient Zinc Limitation

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Laura E. Hesse ◽  
Zachery R. Lonergan ◽  
William N. Beavers ◽  
Eric P. Skaar
Keyword(s):  
Acinetobacter Baumannii ◽  
Defense Mechanisms ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
World Health ◽  
Content Type ◽  
Nutritional Immunity ◽  
Essential Nutrient ◽  
Health Organization

ABSTRACT Acinetobacter baumannii is an opportunistic bacterial pathogen capable of causing a variety of infections, including pneumonia, sepsis, wound, and burn infections. A. baumannii is an increasing threat to public health due to the prevalence of multidrug-resistant strains, leading the World Health Organization to declare A. baumannii a “Priority 1: Critical” pathogen, for which the development of novel antimicrobials is desperately needed. Zinc (Zn) is an essential nutrient that pathogenic bacteria, including A. baumannii, must acquire from their hosts in order to survive. Consequently, vertebrate hosts have defense mechanisms to sequester Zn from invading bacteria through a process known as nutritional immunity. Here, we describe a Zn uptake (Znu) system that enables A. baumannii to overcome this host-imposed Zn limitation. The Znu system consists of an inner membrane ABC transporter and an outer membrane TonB-dependent receptor. Strains of A. baumannii lacking any individual Znu component are unable to grow in Zn-starved conditions, including in the presence of the host nutritional immunity protein calprotectin. The Znu system contributes to Zn-limited growth by aiding directly in the uptake of Zn into A. baumannii cells and is important for pathogenesis in murine models of A. baumannii infection. These results demonstrate that the Znu system allows A. baumannii to subvert host nutritional immunity and acquire Zn during infection.

scholarly journals Aminoglycoside Heteroresistance inAcinetobacter baumanniiAB5075

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Sarah E. Anderson ◽  
Edgar X. Sherman ◽  
David S. Weiss ◽  
Philip N. Rather
Keyword(s):  
Acinetobacter Baumannii ◽  
Population Analysis ◽  
World Health ◽  
Dependent Manner ◽  
Aminoglycoside Resistance ◽  
Gene Encoding ◽  
Integrase Gene ◽  
Content Type ◽  
Mechanistic Basis ◽  
Health Organization

ABSTRACTHeteroresistance is a phenomenon where a subpopulation of cells exhibits higher levels of antibiotic resistance than the general population. Analysis of tobramycin resistance inAcinetobacter baumanniiAB5075 using Etest strips demonstrated that colonies with increased resistance arose at high frequency within the zone of growth inhibition. The presence of a resistant subpopulation was confirmed by population analysis profiling (PAP). The tobramycin-resistant subpopulation was cross resistant to gentamicin but not amikacin. The increased tobramycin resistance phenotype was highly unstable, and cells reverted to a less resistant population at frequencies of 60 to 90% after growth on nonselective media. Furthermore, the frequency of the resistant subpopulation was not increased by preincubation with subinhibitory concentrations of tobramycin. The tobramycin-resistant subpopulation was shown to replicate during the course of antibiotic treatment, demonstrating that these were not persister cells. InA. baumanniiAB5075, a large plasmid (p1AB5075) carriesaadB, a 2″-nucleotidyltransferase that confers resistance to both tobramycin and gentamicin but not amikacin. TheaadBgene is part of an integron and is carried adjacent to four additional resistance genes that are all flanked by copies of an integrase gene. In isolates with increased resistance, this region was highly amplified in a RecA-dependent manner. However, in arecAmutant, colonies with unstable tobramycin resistance arose by a mechanism that did not involve amplification of this region. These data indicate that tobramycin heteroresistance occurs by at least two mechanisms inA. baumannii, and future studies to determine its effect on patient outcomes are warranted.IMPORTANCEAcinetobacter baumanniihas become an important pathogen in hospitals worldwide, where the incidence of these infections has been increasing.A. baumanniiinfections have become exceedingly difficult to treat due to a rapid increase in the frequency of multidrug- and pan-resistant isolates. This has prompted the World Health Organization to listA. baumanniias the top priority for the research and development of new antibiotics. This study reports for the first time a detailed analysis of aminoglycoside heteroresistance inA. baumannii. We define the mechanistic basis for heteroresistance, where theaadB(ant2″)Iagene encoding an aminoglycoside adenylyltransferase becomes highly amplified in a RecA-dependent manner. Remarkably, this amplification of 20 to 40 copies occurs stochastically in 1/200 cells in the absence of antibiotic selection. In addition, we provide evidence for a second RecA-independent mechanism for aminoglycoside heteroresistance. This study reveals that aminoglycoside resistance inA. baumanniiis far more complex than previously realized and has important implications for the use of aminoglycosides in treatingA. baumanniiinfections.

scholarly journals Avibactam Restores the Susceptibility of Clinical Isolates of Stenotrophomonas maltophilia to Aztreonam

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Maria F. Mojica ◽  
Krisztina M. Papp-Wallace ◽  
Magdalena A. Taracila ◽  
Melissa D. Barnes ◽  
Joseph D. Rutter ◽  
...  
Keyword(s):  
Stenotrophomonas Maltophilia ◽  
Opportunistic Pathogen ◽  
Multidrug Resistant ◽  
World Health ◽  
Combination Therapies ◽  
Content Type ◽  
Medical Need ◽  
The World ◽  
Health Organization

ABSTRACT Stenotrophomonas maltophilia is an emerging opportunistic pathogen, classified by the World Health Organization as one of the leading multidrug-resistant organisms in hospital settings. The need to discover novel compounds and/or combination therapies for S. maltophilia is urgent. We demonstrate the in vitro efficacy of aztreonam-avibactam (ATM-AVI) against S. maltophilia and kinetically characterize the inhibition of the L2 β-lactamase by avibactam. ATM-AVI overcomes aztreonam resistance in selected clinical strains of S. maltophilia, addressing an unmet medical need.

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 Loci Encoding Compounds Potentially Active against Drug-Resistant Pathogens amidst a Decreasing Pool of Novel Antibiotics

2019 ◽  
Vol 85 (23) ◽  
Author(s):  
Joseph Basalla ◽  
Payel Chatterjee ◽  
Elizabeth Burgess ◽  
Mahnur Khan ◽  
Emily Verbrugge ◽  
...  
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Multidrug Resistant ◽  
Antagonistic Activity ◽  
World Health ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Health Organization ◽  
Novel Antibiotics

ABSTRACT Since the discovery of penicillin, microbes have been a source of antibiotics that inhibit the growth of pathogens. However, with the evolution of multidrug-resistant (MDR) strains, it remains unclear if there is an abundant or limited supply of natural products to be discovered that are effective against MDR isolates. To identify strains that are antagonistic to pathogens, we examined a set of 471 globally derived environmental Pseudomonas strains (env-Ps) for activity against a panel of 65 pathogens including Achromobacter spp., Burkholderia spp., Pseudomonas aeruginosa, and Stenotrophomonas spp. isolated from the lungs of cystic fibrosis (CF) patients. From more than 30,000 competitive interactions, 1,530 individual inhibitory events were observed. While strains from water habitats were not proportionate in antagonistic activity, MDR CF-derived pathogens (CF-Ps) were less susceptible to inhibition by env-Ps, suggesting that fewer natural products are effective against MDR strains. These results advocate for a directed strategy to identify unique drugs. To facilitate discovery of antibiotics against the most resistant pathogens, we developed a workflow in which phylogenetic and antagonistic data were merged to identify strains that inhibit MDR CF-Ps and subjected those env-Ps to transposon mutagenesis. Six different biosynthetic gene clusters (BGCs) were identified from four strains whose products inhibited pathogens including carbapenem-resistant P. aeruginosa. BGCs were rare in databases, suggesting the production of novel antibiotics. This strategy can be utilized to facilitate the discovery of needed antibiotics that are potentially active against the most drug-resistant pathogens. IMPORTANCE Carbapenem-resistant P. aeruginosa is difficult to treat and has been deemed by the World Health Organization as a priority one pathogen for which antibiotics are most urgently needed. Although metagenomics and bioinformatic studies suggest that natural bacteria remain a source of novel compounds, the identification of genes and their products specific to activity against MDR pathogens remains problematic. Here, we examine water-derived pseudomonads and identify gene clusters whose compounds inhibit CF-derived MDR pathogens, including carbapenem-resistant P. aeruginosa.

scholarly journals Multidrug-Resistant Bacterial Foodborne Pathogens: Impact on Human Health and Economy

2020 ◽  
Author(s):  
Lilia M. Mancilla-Becerra ◽  
Teresa Lías-Macías ◽  
Cristina L. Ramírez-Jiménez ◽  
Jeannette Barba León
Keyword(s):  
Drug Resistance ◽  
Foodborne Pathogens ◽  
Food Production ◽  
Pathogenic Bacteria ◽  
Multidrug Resistant ◽  
World Health ◽  
Economic Losses ◽  
Bacterial Drug Resistance ◽  
Health Organization ◽  
Therapeutic Doses

The drug abuse known to occur during growth of animals intended for food production, because of their use as either a prophylactic or therapeutic treatment, promotes the emergence of bacterial drug resistance. It has been reported that at least 25% of the foodborne isolates show drug resistance to one or more classes of antimicrobials (FAO 2018). There are diverse mechanisms that promote drug resistance. It is known that the use of sub-therapeutic doses of antibiotics in animals intended for food production promotes mutations of some chromosomal genes such as gyrA-parC and mphA, which are responsible for quinolone and azithromycin resistance, respectively. Also, the horizontal transfer of resistance genes as groups (“cassettes”) or plasmids makes the spread of resistance to different bacterial genera possible, among which there could be pathogens. The World Health Organization considers the emergence of multidrug-resistant pathogenic bacteria as a health problem, since the illnesses caused by them complicate the treatment and increase the morbidity and mortality rates. The complication in the illness treatment caused by a multidrug-resistant pathogen causes economic losses to patients for the payment of long stays in hospitals and also causes economic losses to companies due to the absenteeism of their workers.

scholarly journals Exploring the Antimicrobial Action of Quaternary Amines against Acinetobacter baumannii

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Gregory A. Knauf ◽  
Ashley L. Cunningham ◽  
Misha I. Kazi ◽  
Ian M. Riddington ◽  
Alexander A. Crofts ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Acinetobacter Baumannii ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogen ◽  
Multidrug Resistant ◽  
Antimicrobial Action ◽  
Quaternary Amine ◽  
Low Concentrations ◽  
High Concentrations ◽  
Amine Compounds

ABSTRACTQuaternary amine compounds (QAC) are potent antimicrobials used to prevent the spread of pathogenic bacteria. While they are known for their membrane-damaging properties, QAC action has been suggested to extend beyond the surface to intracellular targets. Here we characterize the range of action of the QAC biocide benzalkonium chloride (BZK) against the bacterial pathogenAcinetobacter baumannii. At high concentrations, BZK acts through membrane disruption, but at low concentrations we show that wide-spread protein aggregation is associated with BZK-induced cell death. Resistance to BZK is found to develop through ribosomal protein mutations that protectA. baumanniiagainst BZK-induced protein aggregation. The multifunctional impact of BZK led us to discover that alternative QAC structures, with low human toxicity, retain potent action against multidrug-resistantA. baumannii,Staphylococcus aureus, andClostridium difficileand present opportunities for their development as antibiotics.IMPORTANCEQuaternary amine compounds (QACs) are widely used to prevent the spread of bacterial pathogens, but our understanding of their mode of action is incomplete. Here we describe disruption of bacterial proteostasis as an unrecognized action of QAC antimicrobial action and uncover the potential of diverse QAC structures to act as multitarget antibiotics.

scholarly journals Methicillin-Resistant Staphylococcus aureus in Hospitals: Latest Trends and Treatments Based on Bacteriophages

2019 ◽  
Vol 57 (12) ◽  
Author(s):  
Andrea Álvarez ◽  
Lucía Fernández ◽  
Diana Gutiérrez ◽  
Beatriz Iglesias ◽  
Ana Rodríguez ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Pathogenic Bacteria ◽  
World Health ◽  
Natural Phenomenon ◽  
Methicillin Resistant ◽  
Content Type ◽  
Wide Range ◽  
Mrsa Strains ◽  
Health Organization

ABSTRACT Even though antibiotic resistance in bacteria is a natural phenomenon, the alarming increase in pathogenic bacteria refractory to a wide range of antimicrobials is attracting attention worldwide. Indeed, the World Health Organization (WHO) has recently published a list of priority pathogens for which new antimicrobial alternatives are urgently needed. Among these pathogens, methicillin-resistant Staphylococcus aureus (MRSA) strains are perhaps the best known by the general public. In addition to its potential to acquire antibiotic resistance, S. aureus can produce a large number of virulence factors, such as hemolysins, enterotoxins, and proteases, and exhibits the ability to form biofilms as well as to evolve into different clones that can spread and colonize new environments. This review provides a brief overview of the latest options in antibacterial therapies, mainly focusing on phage therapy. In this regard, the current stage of research about antimicrobial compounds based on bacteriophages and endolysins against MRSA infections is shown and discussed.

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 Resources for Genetic and Genomic Analysis of Emerging Pathogen Acinetobacter baumannii

2015 ◽  
Vol 197 (12) ◽  
pp. 2027-2035 ◽  
Author(s):  
Larry A. Gallagher ◽  
Elizabeth Ramage ◽  
Eli J. Weiss ◽  
Matthew Radey ◽  
Hillary S. Hayden ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Large Scale ◽  
Experimental Studies ◽  
Bacterial Pathogen ◽  
Genomic Analysis ◽  
Multidrug Resistant ◽  
Health Care Facilities ◽  
High Coverage ◽  
Content Type ◽  
Genome Scale

ABSTRACTAcinetobacter baumanniiis a Gram-negative bacterial pathogen notorious for causing serious nosocomial infections that resist antibiotic therapy. Research to identify factors responsible for the pathogen's success has been limited by the resources available for genome-scale experimental studies. This report describes the development of several such resources forA. baumanniistrain AB5075, a recently characterized wound isolate that is multidrug resistant and displays robust virulence in animal models. We report the completion and annotation of the genome sequence, the construction of a comprehensive ordered transposon mutant library, the extension of high-coverage transposon mutant pool sequencing (Tn-seq) to the strain, and the identification of the genes essential for growth on nutrient-rich agar. These resources should facilitate large-scale genetic analysis of virulence, resistance, and other clinically relevant traits that makeA. baumanniia formidable public health threat.IMPORTANCEAcinetobacter baumanniiis one of six bacterial pathogens primarily responsible for antibiotic-resistant infections that have become the scourge of health care facilities worldwide. Eliminating such infections requires a deeper understanding of the factors that enable the pathogen to persist in hospital environments, establish infections, and resist antibiotics. We present a set of resources that should accelerate genome-scale genetic characterization of these traits for a reference isolate ofA. baumanniithat is highly virulent and representative of current outbreak strains.

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