scholarly journals Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Larry A. Gallagher ◽  
Samuel A. Lee ◽  
Colin Manoil
Keyword(s):  
Antibiotic Resistance ◽  
Core Genome ◽  
Important Class ◽  
The Core ◽  
Bacterial Antibiotic Resistance ◽  
A Genome ◽  
In The Wild ◽  
Resistance Island ◽  
High Level ◽  
Level Resistance

ABSTRACT Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen Acinetobacter baumannii. Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis. IMPORTANCE The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known. IMPORTANCE The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known.

scholarly journals Virulence and antibiotic resistance plasticity of Arcobacter butzleri: insights on the genomic diversity of an emerging human pathogen

2019 ◽  
Author(s):  
Joana Isidro ◽  
Susana Ferreira ◽  
Miguel Pinto ◽  
Fernanda Domingues ◽  
Mónica Oleastro ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Comparative Genomics ◽  
Core Genome ◽  
Human Pathogen ◽  
Genome Diversity ◽  
Pathogenic Potential ◽  
The Core ◽  
Pan Genome ◽  
Arcobacter Butzleri ◽  
Genome Scale

AbstractArcobacter butzleri is a food and waterborne bacteria and an emerging human pathogen, frequently displaying a multidrug resistant character. Still, no comprehensive genome-scale comparative analysis has been performed so far, which has limited our knowledge on A. butzleri diversification and pathogenicity. Here, we performed a deep genome analysis of A. butzleri focused on decoding its core- and pan-genome diversity and specific genetic traits underlying its pathogenic potential and diverse ecology. In total, 49 A. butzleri strains (collected from human, animal, food and environmental sources) were screened.A. butzleri (genome size 2.07-2.58 Mbp) revealed a large open pan-genome with 7474 genes (about 50% being singletons) and a small core-genome with 1165 genes. The core-genome is highly diverse (≥55% of the core genes presenting at least 40/49 alleles), being enriched with genes associated with housekeeping functions. In contrast, the accessory genome presented a high proportion of loci with an unknown function, also being particularly overrepresented by genes associated with defence mechanisms. A. butzleri revealed a plastic virulome (including newly identified determinants), marked by the differential presence of multiple adaptation-related virulence factors, such as the urease cluster ureD(AB)CEFG (phenotypically confirmed), the hypervariable hemagglutinin-encoding hecA, a putative type I secretion system (T1SS) harboring another agglutinin potentially related to adherence and a novel VirB/D4 T4SS likely linked to interbacterial competition and cytotoxicity. In addition, A. butzleri harbors a large repertoire of efflux pumps (EPs) (ten “core” and nine differentially present) and other antibiotic resistant determinants. We provide the first description of a genetic determinant of macrolides resistance in A. butzleri, by associating the inactivation of a TetR repressor (likely regulating an EP) with erythromycin resistance. Fluoroquinolones resistance correlated with the Thr-85-Ile substitution in GyrA and ampicillin resistance was linked to an OXA-15-like β-lactamase. Remarkably, by decoding the polymorphism pattern of the porin- and adhesin-encoding main antigen PorA, this study strongly supports that this pathogen is able to exchange porA as a whole and/or hypervariable epitope-encoding regions separately, leading to a multitude of chimeric PorA presentations that can impact pathogen-host interaction during infection. Ultimately, our unprecedented screening of short sequence repeats detected potential phase-variable genes related to adaptation and host/environment interaction, such as lipopolysaccharide modification and motility/chemotaxis, suggesting that phase variation likely modulate A. butzleri key adaptive functions.In summary, this study constitutes a turning point on A. butzleri comparative genomics revealing that this human gastrointestinal pathogen is equipped with vast virulence and antibiotic resistance arsenals, which, coupled with its remarkable core- and pan-genome diversity, opens a multitude of phenotypic fingerprints for environmental/host adaptation and pathogenicity.IMPACT STATEMENTDiarrhoeal diseases are the most common cause of human illness caused by foodborne hazards, but the surveillance of diarrhoeal diseases is biased towards the most commonly searched infectious agents (namely Campylobacter jejuni and C. coli). In fact, other less studied pathogens are frequently found as the etiological agent when refined non-selective culture conditions are applied. A hallmark example is the diarrhoeal-causing Arcobacter butzleri which, despite being also associated with extra-intestinal diseases, such as bacteremia in humans and mastitis in animals, and displaying high rates of antibiotic resistance, has not yet been profoundly investigated regarding its epidemiology, diversity and pathogenicity. To overcome the general lack of knowledge on A. butzleri comparative genomics, we provide the first comprehensive genome-scale analysis of A. butzleri focused on exploring the intraspecies virulome content and diversity, resistance determinants, as well as how this pathogen shapes its genome towards ecological adaptation and host invasion. The unveiled scenario of A. butzleri rampant diversity and plasticity reinforces the pathogenic potential of this food and waterborne hazard, while opening multiple research lines that will certainly contribute to the future development of more robust species-oriented diagnostics and molecular surveillance of A. butzleri.DATA SUMMARYA. butzleri raw sequence reads generated in the present study were deposited in the European Nucleotide Archive (ENA) (BioProject PRJEB34441). The assembled contigs (.fasta and .gbk files), the nucleotide sequences of the predicted transcripts (CDS, rRNA, tRNA, tmRNA, misc_RNA) (.ffn files) and the respective amino acid sequences of the translated CDS sequences (.faa files) are available at http://doi.org/10.5281/zenodo.3434222. Detailed ENA accession numbers, as well as the draft genome statistics are described in Table S1.

scholarly journals Long-Term Shifts in Patterns of Antibiotic Resistance in Enteric Bacteria

2000 ◽  
Vol 66 (12) ◽  
pp. 5406-5409 ◽  
Author(s):  
Tara Houndt ◽  
Howard Ochman
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Species ◽  
Natural Populations ◽  
Enteric Bacteria ◽  
Commercial Application ◽  
Before And After ◽  
Resistance Patterns ◽  
High Level ◽  
Antibiotic Resistance Patterns ◽  
Level Resistance

ABSTRACT Several mechanisms are responsible for the ability of microorganisms to tolerate antibiotics, and the incidence of resistance to these compounds within bacterial species has increased since the commercial use of antibiotics became widespread. To establish the extent of and changes in the diversity of antibiotic resistance patterns in natural populations, we determined the MICs of five antibiotics for collections of enteric bacteria isolated from diverse hosts and geographic locations and during periods before and after commercial application of antibiotics began. All of the pre-antibiotic era strains were susceptible to high levels of these antibiotics, whereas 20% of strains from contemporary populations ofEscherichia coli and Salmonella entericadisplayed high-level resistance to at least one of the antibiotics. In addition to the increase in the frequency of high-level resistance, background levels, conferred by genes providing nonspecific low-level resistance to multiple antibiotics, were significantly higher among contemporary strains. Changes in the incidence and levels of antibiotic resistance are not confined to particular segments of the bacterial population and reflect responses to the increased exposure of bacteria to antimicrobial compounds over the past several decades.

scholarly journals Genetic Basis of Antibiotic Resistance in Streptococcus agalactiae Strains Isolated in a French Hospital

2003 ◽  
Vol 47 (2) ◽  
pp. 794-797 ◽  
Author(s):  
Claire Poyart ◽  
Laurence Jardy ◽  
Gilles Quesne ◽  
Patrick Berche ◽  
Patrick Trieu-Cuot
Keyword(s):  
Antibiotic Resistance ◽  
Streptococcus Agalactiae ◽  
Genetic Basis ◽  
Group B Streptococci ◽  
Resistant Strains ◽  
French Hospital ◽  
Group B ◽  
High Level ◽  
Level Resistance

ABSTRACT The genetic basis of antibiotic resistance in 113 unrelated group B streptococci was studied by PCR. Ninety-four strains were resistant to tetracycline-minocycline, and tet(M) was detected in 85% of these isolates. Seventeen erythromycin-resistant strains contained the erm(B), erm(TR), or mef(A) gene. Eleven strains exhibited high-level resistance to kanamycin due to the presence of the aphA3 gene; eight of these strains were also highly resistant to streptomycin; aad-6-related sequences were detected in seven strains.

scholarly journals A catalytic switch uncovered in gentamicin resistance kinase APH(2'')-Ia

2014 ◽  
Vol 70 (a1) ◽  
pp. C704-C704
Author(s):  
Shane Caldwell ◽  
Albert Berghuis
Keyword(s):  
Antibiotic Resistance ◽  
Kinase Domain ◽  
Aminoglycoside Resistance ◽  
Conformational Switch ◽  
Bacterial Populations ◽  
Gentamicin Resistance ◽  
High Level ◽  
Hydrolysis Of ◽  
Evolutionary Fitness ◽  
Level Resistance

The APH(2'')-Ia domain of the bifunctional aminoglycoside resistance enzyme AAC(6')-Ie/APH(2'')-Ia confers high-level resistance to aminoglycoside antibiotics. Crystal structures of this kinase domain in complex with GTP analogues and acceptor substrates have uncovered a surprising conformational bistability of the GTP substrate, which may reduce futile hydrolysis of the cofactor by the enzyme. This conformational switch is influenced by the binding of aminoglycosides, and may represent an adaptive feature of the enzyme, improving its evolutionary fitness in bacterial populations. This mechanism combines with a remarkable flexibility observed in the binding of diverse aminoglycoside substrates to make this enzyme a formidable antibiotic resistance machine.

scholarly journals Induction of Multidrug Resistance Mechanism in Escherichia coli Biofilms by Interplay between Tetracycline and Ampicillin Resistance Genes

2009 ◽  
Vol 53 (11) ◽  
pp. 4628-4639 ◽  
Author(s):  
Thithiwat May ◽  
Akinobu Ito ◽  
Satoshi Okabe
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Marker Genes ◽  
Ampicillin Resistance ◽  
High Level ◽  
Biofilm Development ◽  
Level Resistance

ABSTRACT Biofilms gain resistance to various antimicrobial agents, and the presence of antibiotic resistance genes is thought to contribute to a biofilm-mediated antibiotic resistance. Here we showed the interplay between the tetracycline resistance efflux pump TetA(C) and the ampicillin resistance gene (bla TEM-1) in biofilms of Escherichia coli harboring pBR322 in the presence of the mixture of ampicillin and tetracycline. E. coli in the biofilms could obtain the high-level resistance to ampicillin, tetracycline, penicillin, erythromycin, and chloramphenicol during biofilm development and maturation as a result of the interplay between the marker genes on the plasmids, the increase of plasmid copy number, and consequently the induction of the efflux systems on the bacterial chromosome, especially the EmrY/K and EvgA/S pumps. In addition, we characterized the overexpression of the TetA(C) pump that contributed to osmotic stress response and was involved in the induction of capsular colanic acid production, promoting formation of mature biofilms. However, this investigated phenomenon was highly dependent on the addition of the subinhibitory concentrations of antibiotic mixture, and the biofilm resistance behavior was limited to aminoglycoside antibiotics. Thus, marker genes on plasmids played an important role in both resistance of biofilm cells to antibiotics and in formation of mature biofilms, as they could trigger specific chromosomal resistance mechanisms to confer a high-level resistance during biofilm formation.

scholarly journals Integron gene cassettes harboring novel variants of d-alanine-d-alanine ligase confer high-level resistance to d-cycloserine

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Md. Ajijur Rahman ◽  
Frank Kaiser ◽  
Shirin Jamshidi ◽  
Marta Freitas Monteiro ◽  
Khondaker Miraz Rahman ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Atomic Scale ◽  
Phenotypic Change ◽  
Plant Metabolites ◽  
Healthy Human ◽  
Gene Cassettes ◽  
Evolutionary Selection ◽  
Novel Variants ◽  
High Level ◽  
Level Resistance

AbstractAntibiotic resistance poses an increasing threat to global health. To tackle this problem, the identification of principal reservoirs of antibiotic resistance genes (ARGs) plus an understanding of drivers for their evolutionary selection are important. During a PCR-based screen of ARGs associated with integrons in saliva-derived metagenomic DNA of healthy human volunteers, two novel variants of genes encoding a d-alanine-d-alanine ligase (ddl6 and ddl7) located within gene cassettes in the first position of a reverse integron were identified. Treponema denticola was identified as the likely host of the ddl cassettes. Both ddl6 and ddl7 conferred high level resistance to d-cycloserine when expressed in Escherichia coli with ddl7 conferring four-fold higher resistance to D-cycloserine compared to ddl6. A SNP was found to be responsible for this difference in resistance phenotype between the two ddl variants. Molecular dynamics simulations were used to explain the mechanism of this phenotypic change at the atomic scale. A hypothesis for the evolutionary selection of ddl containing integron gene cassettes is proposed, based on molecular docking of plant metabolites within the ATP and d-cycloserine binding pockets of Ddl.

scholarly journals Prevalence and Antibiotic Resistance Profile of Pseudomonas aeruginosa from Hospital Sinks in South Western Nigeria

2019 ◽  
pp. 1-7
Author(s):  
Olayinka Oluyemi Oluranti ◽  
Chiamaka Ifeoma Ubanagu ◽  
Olukunle Oluwapamilerin Oluwasemowo ◽  
Omowunmi Temidayo Akinola ◽  
Yewande Tolulope Nejo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Opportunistic Pathogens ◽  
Resistance Profile ◽  
Antibiotic Resistance Profile ◽  
Clade B ◽  
Hospital Infection Control ◽  
Medical Importance ◽  
High Level ◽  
Level Resistance

Background: Pseudomonas aeruginosa (P. aeruginosa) has been identified as a major pathogen in man, causing both opportunistic and nosocomial infections. Pseudomonas is a ubiquitous organism often isolated from various surfaces, which have the ability to form biofilms, making it a unique organism of medical importance. Objective: The aim of this study is to determine the prevalence of P. aeruginosa isolated from hospital sinks and their antibiotic resistance profile. Methods: Swab samples were collected from hospital sinks in five health care institutions and inoculated unto Nutrient agar and sub cultured on cetrimide agar. Isolated P. aeruginosa were subjected to antibiotic susceptibility testing using CSLI guidelines. Results: Prevalence of Pseudomonas species isolated from the hospitals’ sinks was 56%. High level resistance was recorded against amoxicillin/clavunalate, ampicillin and ceftriaxone. Resistance profile of the isolates clustered into two main clades clade A and clade B, with clade A isolates recording a higher MARI score. Conclusion: Isolation of multi-resistant P. aeruginosa from hospital sinks calls for improved hospital infection control practices. We advocate for inclusion of environmental surveillance, particularly of opportunistic pathogens in our hospitals.

scholarly journals Antibiotic resistance among enterococci isolated from clinical specimens between 1953 and 1954.

1997 ◽  
Vol 41 (7) ◽  
pp. 1598-1600 ◽  
Author(s):  
B A Atkinson ◽  
A Abu-Al-Jaibat ◽  
D J LeBlanc
Keyword(s):  
Antibiotic Resistance ◽  
Genomic Dna ◽  
Beta Lactamase ◽  
Clinical Specimens ◽  
High Level ◽  
Group D ◽  
Level Resistance

Two hundred twenty group D streptococci isolated from 1953 to 1954 from patients in the Washington, D.C., area were characterized. All were susceptible to ampicillin, vancomycin, and gentamicin; none produced beta-lactamase activity. High-level resistance to streptomycin was expressed by 117 strains, and 2 strains were resistant to >8 microg of chloramphenicol per ml. Three isolates were resistant to both erythromycin and lincomycin, and DNA from these hybridized to an ermAM probe. Of 118 strains resistant to tetracycline and minocycline, genomic DNA from 63 was examined for homology to tet(M), tet(O), and tet(S). DNA from 20 strains hybridized to tet(M), DNA from 37 strains hybridized to tet(S), and DNA from none of the strains hybridized to tet(O).

scholarly journals Bacterial antibiotic resistance development and mutagenesis following exposure to subinhibitory concentrations of fluoroquinolones in vitro: a systematic review of the literature

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Carly Ching ◽  
Ebiowei S F Orubu ◽  
Indorica Sutradhar ◽  
Veronika J Wirtz ◽  
Helen W Boucher ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Genetic Regulation ◽  
Experimental Studies ◽  
Resistance Mechanisms ◽  
Bacterial Antibiotic Resistance ◽  
Resistance Patterns ◽  
Antibiotic Efficacy ◽  
Level Resistance

Abstract Background Understanding social and scientific drivers of antibiotic resistance is critical to help preserve antibiotic efficacy. These drivers include exposure to subinhibitory antibiotic concentrations in the environment and clinic. Objectives To summarize and quantify the relationship between subinhibitory fluoroquinolone exposure and antibiotic resistance and mutagenesis to better understand resistance patterns and mechanisms. Methods Following PRISMA guidelines, PubMed, Web of Science and Embase were searched for primary in vitro experimental studies on subinhibitory fluoroquinolone exposure and bacterial antibiotic resistance and mutagenesis, from earliest available dates through to 2018 without language limitation. A specifically developed non-weighted tool was used to assess risk of bias. Results Evidence from 62 eligible studies showed that subinhibitory fluoroquinolone exposure results in increased resistance to the selecting fluoroquinolone. Most increases in MIC were low (median minimum of 3.7-fold and median maximum of 32-fold) and may not be considered clinically relevant. Mechanistically, resistance is partly explained by target mutations but also changes in drug efflux. Collaterally, resistance to other fluoroquinolones and unrelated antibiotic classes also develops. The mean ± SD quality score for all studies was 2.6 ± 1.8 with a range of 0 (highest score) to 7 (lowest score). Conclusions Low and moderate levels of resistance and efflux changes can create an opportunity for higher-level resistance or MDR. Future studies, to elucidate the genetic regulation of specific resistance mechanisms, and increased policies, including surveillance of low-level resistance changes or genomic surveillance of efflux pump genes and regulators, could serve as a predictor of MDR development.

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