scholarly journals Genomic Insights into Drug Resistance Determinants in Cedecea neteri, A Rare Opportunistic Pathogen

2021 ◽  
Vol 9 (8) ◽  
pp. 1741
Author(s):  
Dorothea K. Thompson ◽  
Stephen M. Sharkady
Keyword(s):  
Drug Resistance ◽  
Sequence Data ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Whole Genome Sequence ◽  
Multidrug Efflux ◽  
Resistance Determinants ◽  
Multidrug Efflux Pumps ◽  
Novel Variant ◽  
Immunocompromised Hosts

Cedecea, a genus in the Enterobacteriaceae family, includes several opportunistic pathogens reported to cause an array of sporadic acute infections, most notably of the lung and bloodstream. One species, Cedecea neteri, is associated with cases of bacteremia in immunocompromised hosts and has documented resistance to different antibiotics, including β-lactams and colistin. Despite the potential to inflict serious infections, knowledge about drug resistance determinants in Cedecea is limited. In this study, we utilized whole-genome sequence data available for three environmental strains (SSMD04, M006, ND14a) of C. neteri and various bioinformatics tools to analyze drug resistance genes in this bacterium. All three genomes harbor multiple chromosome-encoded β-lactamase genes. A deeper analysis of β-lactamase genes in SSMD04 revealed four metallo-β-lactamases, a novel variant, and a CMY/ACT-type AmpC putatively regulated by a divergently transcribed AmpR. Homologs of known resistance-nodulation-cell division (RND)-type multidrug efflux pumps such as OqxB, AcrB, AcrD, and MdtBC were also identified. Genomic island prediction for SSMD04 indicated that tolC, involved in drug and toxin export across the outer membrane of Gram-negative bacteria, was acquired by a transposase-mediated genetic transfer mechanism. Our study provides new insights into drug resistance mechanisms of an environmental microorganism capable of behaving as a clinically relevant opportunistic pathogen.

scholarly journals Diversity and Distribution of Resistance Markers in Pseudomonas aeruginosa International High-Risk Clones

2021 ◽  
Vol 9 (2) ◽  
pp. 359
Author(s):  
Béla Kocsis ◽  
Dániel Gulyás ◽  
Dóra Szabó
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Risk ◽  
Sequence Data ◽  
Resistance Mechanisms ◽  
Whole Genome Sequence ◽  
Beta Lactamases ◽  
Resistance Determinants ◽  
Causative Agents ◽  
Surveillance Programs ◽  
Hospital Acquired

Pseudomonas aeruginosa high-risk clones are disseminated worldwide and they are common causative agents of hospital-acquired infections. In this review, we will summarize available data of high-risk P. aeruginosa clones from confirmed outbreaks and based on whole-genome sequence data. Common feature of high-risk clones is the production of beta-lactamases and among metallo-beta-lactamases NDM, VIM and IMP types are widely disseminated in different sequence types (STs), by contrast FIM type has been reported in ST235 in Italy, whereas GIM type in ST111 in Germany. In the case of ST277, it is most frequently detected in Brazil and it carries a resistome linked to blaSPM. Colistin resistance develops among P. aeruginosa clones in a lesser extent compared to other resistance mechanisms, as ST235 strains remain mainly susceptible to colistin however, some reports described mcr positive P. aeurigonsa ST235. Transferable quinolone resistance determinants are detected in P. aeruginosa high-risk clones and aac(6′)-Ib-cr variant is the most frequently reported as this determinant is incorporated in integrons. Additionally, qnrVC1 was recently detected in ST773 in Hungary and in ST175 in Spain. Continuous monitoring and surveillance programs are mandatory to track high-risk clones and to analyze emergence of novel clones as well as novel resistance determinants.

scholarly journals Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

2009 ◽  
Vol 22 (4) ◽  
pp. 582-610 ◽  
Author(s):  
Philip D. Lister ◽  
Daniel J. Wolter ◽  
Nancy D. Hanson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Opportunistic Pathogen ◽  
Efflux Pumps ◽  
Resistance Mechanisms ◽  
Clinical Impact ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pumps ◽  
Outer Membrane Porin ◽  
Complex Regulation ◽  
Difficult Challenge

SUMMARY Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

scholarly journals Variation in Streptomycin Resistance Mechanisms in Clavibacter michiganensis

2019 ◽  
Vol 109 (11) ◽  
pp. 1849-1858
Author(s):  
Qingyang Lyu ◽  
Kaihong Bai ◽  
Yumin Kan ◽  
Na Jiang ◽  
Shree P. Thapa ◽  
...  
Keyword(s):  
Aminoglycoside Antibiotic ◽  
Resistance Mechanisms ◽  
Streptomycin Resistance ◽  
Economic Losses ◽  
Clavibacter Michiganensis ◽  
Multidrug Efflux ◽  
Canker Disease ◽  
Multidrug Efflux Pumps ◽  
Bacterial Canker Of Tomato ◽  
Functional Analyses

Clavibacter michiganensis is the causal agent of bacterial canker of tomato, which causes significant economic losses because of the lack of resistant tomato varieties. Chemical control with streptomycin or cupric bactericides is the last defensive line in canker disease management. Streptomycin is an aminoglycoside antibiotic that inhibits protein synthesis and targets the 30S ribosomal protein RpsL. Streptomycin has been used to control multiple plant bacterial diseases. However, identification and characterization of streptomycin resistance in C. michiganensis have remained unexplored. In this study, a naturally occurring C. michiganensis strain TX-0702 exhibiting spontaneous streptomycin resistance was identified, with a minimum inhibitory concentration of 128 μg/ml. Additionally, an induced streptomycin-resistant strain BT-0505-R was generated by experimental evolution of the sensitive C. michiganensis strain BT-0505. Genome sequencing and functional analyses were used to identify the genes conferring resistance. A point mutation at the 128th nucleotide in the rpsL gene of strain BT-0505-R is responsible for conferring streptomycin resistance. However, in TX-0702, resistance is not attributed to mutation of rpsL, streptomycin inactivation enzymes, or multidrug efflux pumps. The mechanism of resistance in TX-0702 is independent of previously reported bacterial loci. Taken together, these data highlight diverse mechanisms used by a Gram-positive plant pathogenic bacterium to confer antibiotic resistance.

scholarly journals Dehydrozingerone Exhibits Synergistic Antifungal Activities in Combination with Dodecanol against Budding Yeast via the Restriction of Multidrug Resistance

2018 ◽  
Vol 5 (02) ◽  
pp. e61-e67
Author(s):  
Chika Yamawaki ◽  
Yoshihiro Yamaguchi ◽  
Akira Ogita ◽  
Toshio Tanaka ◽  
Ken-ichi Fujita
Keyword(s):  
Drug Resistance ◽  
Antifungal Activity ◽  
Efflux Pump ◽  
Fungal Infections ◽  
Zingiber Officinale ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Yeast Saccharomyces Cerevisiae ◽  
Multidrug Transporters ◽  
Multidrug Efflux Pumps

AbstractDrug resistance in fungal infections has been a more frequent occurrence with the increasing number of immunocompromised patients. In efforts to overcome the problem of fungal drug resistance, we focused on the phenolic compound dehydrozingerone, which is isolated from Zingiber officinale. The effectiveness of this compound on the model yeast Saccharomyces cerevisiae has not been reported. In our study, dehydrozingerone showed a weak antifungal activity against the yeast, but demonstrated a synergistic effect in combination with dodecanol, which typically only restricts cell growth transiently. Efflux of rhodamine 6G through the multidrug efflux pumps was significantly restricted by dehydrozingerone. The transcription level of PDR5, encoding a primary multidrug efflux pump in S. cerevisiae, was enhanced with dodecanol treatment, whereas the level was reduced by dehydrozingerone. These results suggest that dehydrozingerone may be effective for potentiating antifungal activity of other drugs that are expelled from fungi by multidrug transporters like Pdr5p.

scholarly journals The Bile Response Repressor BreR Regulates Expression of the Vibrio cholerae breAB Efflux System Operon

2008 ◽  
Vol 190 (22) ◽  
pp. 7441-7452 ◽  
Author(s):  
Francisca A. Cerda-Maira ◽  
Carol S. Ringelberg ◽  
Ronald K. Taylor
Keyword(s):  
Vibrio Cholerae ◽  
Sodium Dodecyl ◽  
Virulence Gene ◽  
Resistance Mechanisms ◽  
Mrna Levels ◽  
Multidrug Efflux ◽  
Mobility Shift ◽  
Multidrug Efflux Pumps ◽  
Genes Encoding ◽  
Electrophoretic Mobility Shift Assays

ABSTRACT Enteric pathogens have developed several resistance mechanisms to survive the antimicrobial action of bile. We investigated the transcriptional profile of Vibrio cholerae O1 El Tor strain C6706 under virulence gene-inducing conditions in the presence and absence of bile. Microarray analysis revealed that the expression of 119 genes was affected by bile. The mRNA levels of genes encoding proteins involved in transport were increased in the presence of bile, whereas the mRNA levels of genes encoding proteins involved in pathogenesis and chemotaxis were decreased. This study identified genes encoding transcriptional regulators from the TetR family (vexR and breR) and multidrug efflux pumps from the resistance-nodulation-cell division superfamily (vexB and vexD [herein renamed breB]) that were induced in response to bile. Further analysis regarding vexAB and breAB expression in the presence of various antimicrobial compounds established that vexAB was induced in the presence of bile, sodium dodecyl sulfate, or novobiocin and that the induction of breAB was specific to bile. BreR is a direct repressor of the breAB promoter and is able to regulate its own expression, as demonstrated by transcriptional and electrophoretic mobility shift assays (EMSA). The expression of breR and breAB is induced in the presence of the bile salts cholate, deoxycholate, and chenodeoxycholate, and EMSA showed that deoxycholate is able to abolish the formation of BreR-P breR complexes. We propose that deoxycholate is able to interact with BreR and induce a conformational change that interferes with the DNA binding ability of BreR, resulting in breAB and breR expression. These results provide new insight into a transcriptional regulator and a transport system that likely play essential roles in the ability of V. cholerae to resist the action of bile in the host.

scholarly journals High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes

Parasitology ◽  
2013 ◽  
Vol 141 (1) ◽  
pp. 77-82 ◽  
Author(s):  
DAVID HORN
Keyword(s):  
Drug Resistance ◽  
High Throughput ◽  
Drug Targets ◽  
Sequence Data ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Drug Uptake ◽  
Microbial Pathogens ◽  
African Trypanosomes ◽  
Genome Scale

SUMMARYThe availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs.

scholarly journals The Action of Efflux Pump Genes in Conferring Drug Resistance to Klebsiella Species and Their Inhibition

2021 ◽  
Author(s):  
Priyanka Ashwath ◽  
Akhila Dharnappa Sannejal
Keyword(s):  
Drug Resistance ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Acquired Resistance ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Klebsiella Species ◽  
Gram Negative ◽  
Multidrug Efflux Pumps

AbstractNosocomial infections caused by Klebsiella species are characterized by high rates of morbidity and mortality. The emergence of the multidrug-resistant (MDR) and extensive drug-resistant (XDR) Gram-negative bacteria reduces the antibiotic efficacy in the treatment of infections caused by the microorganisms. Management of these infections is often difficult, due to the high frequency of strains resistant to multiple antimicrobial agents. Multidrug efflux pumps play a major role as a mechanism of antimicrobial resistance in Gram-negative pathogens. Efflux systems are significant in conferring intrinsic and acquired resistance to the bacteria. The emergence of increasing drug resistance among Klebsiella pneumoniae nosocomial isolates has limited the therapeutic options for treatment of these infections and hence there is a constant quest for an alternative. In this review, we discuss various resistance mechanisms, focusing on efflux pumps and related genes in conferring resistance to Klebsiella. The role of various efflux pump inhibitors (EPIs) in restoring the antibacterial activity has also been discussed. In specific, antisense oligonucleotides as alternative therapeutics in combatting efflux-mediated resistance in Klebsiella species have focused upon.

scholarly journals Antagonism of Growth Hormone Receptor Suppresses Cancer Growth and Drug Resistance in Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1011-A1012
Author(s):  
Yanrong Qian ◽  
Reetobrata Basu ◽  
Joseph Terry ◽  
Samuel Casey Mathes ◽  
Nathan Arnett ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Melanoma Cells ◽  
Cancer Growth ◽  
Multidrug Efflux ◽  
Liver Cancer Cells ◽  
Multidrug Efflux Pumps

Abstract Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play important roles in different stages of progression and drug resistance in many types of cancers, including breast, colon, endometrial, liver cancer and melanoma. GH receptor (GHR) is highly expressed in melanoma and promotes cancer proliferation and multidrug efflux pumps mediated drug resistance. Knockdown of GHR in melanoma cells significantly increased their drug sensitivity in vitro. Thus, a GHR antagonist could become a therapeutic molecule in suppressing melanoma cancer growth and sensitizing the tumor to chemotherapy in vivo. Here, we used GHR antagonist (GHA) transgenic mice which constitutively express a GHA to specifically suppress GH/IGF-1 axis. We found have circulating IGF-1 level was significantly lowered in these mice as a result of GHR antagonism. Furthermore, the sera from the mice could inhibit the growth of melanoma cells in culture. Recombinant GHA produced in our laboratory was able to suppress the phosphorylation of STAT5, a well-established marker of GH action, and the phosphorylation of MAPK, a critical signaling component of cell growth. The GHA mice were intradermally inoculated with mouse melanoma cells (B16-F10) or subcutaneously inoculated with mouse liver cancer cells (Hepa1-6) to generate syngeneic mouse tumor models. We observed that tumor size and tumor weight were markedly reduced and that phosphorylation of STAT5 and MAPK was suppressed in the livers from these mice. In parallel, the activation of GH signaling and the expression level of various types of multidrug efflux pumps were reduced in these tumors. To test the effect of GHA on drug synergy, the GHA mice or WT controls with liver cancer cells were treated with sorafenib or vehicle. Sorafenib is an FDA-approved tyrosine kinase inhibitor, widely used to treat advanced hepatocarcinoma, but has a reduced efficacy in application due to the multidrug efflux pump ABCG2. In vitro, recombinant bovine GH increased the IC50 of sorafenib and the expression of ABCG2. In vivo, GHA mice treated with sorafenib had the smallest tumors compared with WT mice, or in mice treated with sorafenib or GHA alone. Furthermore, ABCG2 mRNA levels were also suppressed in the liver tumors from GHA mice. All these findings from functional and mechanistic investigations confirm that a GHA or Pegvisomant is effective in cancer treatment in vivo and may be a novel therapeutic strategy or molecule to suppress the tumor growth and to sensitize different types of cancers to anti-cancer therapies. Acknowledgments: This work was supported by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll to J.K.; NIH-R01AG059779, the AMVETS, Edison Biotechnology Institute and Diabetes Institute at Ohio University; OURC funding and Baker Fund to Y.Q.; the PURF Fund and the John J. Kopchick Molecular Cell Biology Undergraduate Student Fund to N.A and J.T.

scholarly journals Pumping out biocides – cause for concern

2010 ◽  
Vol 31 (4) ◽  
pp. 178
Author(s):  
Karl A Hassan ◽  
Sylvia Baltzer ◽  
Ian Paulsen ◽  
Melissa Brown
Keyword(s):  
Active Sites ◽  
Resistance Mechanisms ◽  
Opportunistic Pathogens ◽  
Research Groups ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Active Efflux ◽  
Resistance Determinants ◽  
Intracellular Targets ◽  
Ammonium Compounds

Bacteria employ a number of resistance mechanisms against antimicrobials, commonly including target site modification, antimicrobial degradation and active efflux. Of these mechanisms, efflux is unique in that a single efflux system can confer resistance to a remarkably broad range of structurally dissimilar antibiotics and biocides that have different intracellular targets and modes of action. For example, in the opportunistic pathogens Staphylococcus aureus and Acinetobacter baumannii, single multidrug efflux systems facilitate the extrusion of agents as broad and diverse as quaternary ammonium compounds, intercalating dyes, diamidines, biguanidines, anionic detergents, aminoglycosides, ?-lactams, chloramphenicol, tetracyclines, trimethoprim and fluoroquinolones (Table 1). This promiscuity of substrates, coupled with the genetic linkage of exporter genes with other resistance determinants on transferable elements such as plasmids, raises the possibility of cross and co-resistance to biocides and antibiotics. Furthermore, data generated by our and other research groups clearly demonstrate a remarkable propensity of multidrug efflux systems to bind new substrates following only minor amino acid changes to their active sites.

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