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Academic literature on the topic 'Polymyxin Resistant Pathway'
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Journal articles on the topic "Polymyxin Resistant Pathway"
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Sampson, Timothy R., Xiang Liu, Max R. Schroeder, Colleen S. Kraft, Eileen M. Burd, and David S. Weiss. "Rapid Killing of Acinetobacter baumannii by Polymyxins Is Mediated by a Hydroxyl Radical Death Pathway." Antimicrobial Agents and Chemotherapy 56, no. 11 (August 20, 2012): 5642–49. http://dx.doi.org/10.1128/aac.00756-12.
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ABSTRACTAcinetobacter baumanniiis an opportunistic pathogen that is a cause of clinically significant nosocomial infections. Increasingly, clinical isolates ofA. baumanniiare extensively resistant to numerous antibiotics, and the use of polymyxin antibiotics against these infections is often the final treatment option. Historically, the polymyxins have been thought to kill bacteria through membrane lysis. Here, we present an alternative mechanism based on data demonstrating that polymyxins induce rapid cell death through hydroxyl radical production. Supporting this notion, we found that inhibition of radical production delays the ability of polymyxins to killA. baumannii. Notably, we demonstrate that this mechanism of killing occurs in multidrug-resistant clinical isolates ofA. baumanniiand that this response is not induced in a polymyxin-resistant isolate. This study is the first to demonstrate that polymyxins induce rapid killing ofA. baumanniiand other Gram-negatives through hydroxyl radical production. This significantly augments our understanding of the mechanism of polymyxin action, which is critical knowledge toward the development of adjunctive therapies, particularly given the increasing necessity for treatment with these antibiotics in the clinical setting.
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Li, Mengyao, Mohammad A. K. Azad, Maizbha U. Ahmed, Yan Zhu, Jiangning Song, Fanfan Zhou, Hak-Kim Chan, Tony Velkov, Qi Tony Zhou, and Jian Li. "Polymyxin Induces Significant Transcriptomic Perturbations of Cellular Signalling Networks in Human Lung Epithelial Cells." Antibiotics 11, no. 3 (February 24, 2022): 307. http://dx.doi.org/10.3390/antibiotics11030307.
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Inhaled polymyxins are increasingly used to treat pulmonary infections caused by multidrug-resistant Gram-negative pathogens. We have previously shown that apoptotic pathways, autophagy and oxidative stress are involved in polymyxin-induced toxicity in human lung epithelial cells. In the present study, we employed human lung epithelial cells A549 treated with polymyxin B as a model to elucidate the complex interplay of multiple signalling networks underpinning cellular responses to polymyxin toxicity. Polymyxin B induced toxicity (1.0 mM, 24 h) in A549 cells was assessed by flow cytometry and transcriptomics was performed using microarray. Polymyxin B induced cell death was 19.0 ± 4.2% at 24 h. Differentially expressed genes (DEGs) between the control and polymyxin B treated cells were identified with Student’s t-test. Pathway analysis was conducted with KEGG and Reactome and key hub genes related to polymyxin B induced toxicity were examined using the STRING database. In total we identified 899 DEGs (FDR < 0.01), KEGG and Reactome pathway analyses revealed significantly up-regulated genes related to cell cycle, DNA repair and DNA replication. NF-κB and nucleotide-binding oligomerization domain-like receptor (NOD) signalling pathways were identified as markedly down-regulated genes. Network analysis revealed the top 5 hub genes (i.e., degree) affected by polymyxin B treatment were PLK1(48), CDK20 (46), CCNA2 (42), BUB1 (40) and BUB1B (37). Overall, perturbations of cell cycle, DNA damage and pro-inflammatory NF-κB and NOD-like receptor signalling pathways play key roles in polymyxin-induced toxicity in human lung epithelial cells. Noting that NOD-like receptor signalling represents a group of key sensors for microorganisms and damage in the lung, understanding the mechanism of polymyxin-induced pulmonary toxicity will facilitate the optimisation of polymyxin inhalation therapy in patients.
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Aye, Su Mon, Irene Galani, Mei-Ling Han, Ilias Karaiskos, Darren J. Creek, Yan Zhu, Yu-Wei Lin, Tony Velkov, Helen Giamarellou, and Jian Li. "Lipid A profiling and metabolomics analysis of paired polymyxin-susceptible and -resistant MDR Klebsiella pneumoniae clinical isolates from the same patients before and after colistin treatment." Journal of Antimicrobial Chemotherapy 75, no. 10 (July 22, 2020): 2852–63. http://dx.doi.org/10.1093/jac/dkaa245.
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Abstract Background The increased incidence of polymyxin-resistant MDR Klebsiella pneumoniae has become a major global health concern. Objectives To characterize the lipid A profiles and metabolome differences between paired polymyxin-susceptible and -resistant MDR K. pneumoniae clinical isolates. Methods Three pairs of K. pneumoniae clinical isolates from the same patients were examined [ATH 7 (polymyxin B MIC 0.25 mg/L) versus ATH 8 (64 mg/L); ATH 15 (0.5 mg/L) versus ATH 16 (32 mg/L); and ATH 17 (0.5 mg/L) versus ATH 18 (64 mg/L)]. Lipid A and metabolomes were analysed using LC-MS and bioinformatic analysis was conducted. Results The predominant species of lipid A in all three paired isolates were hexa-acylated and 4-amino-4-deoxy-l-arabinose-modified lipid A species were detected in the three polymyxin-resistant isolates. Significant metabolic differences were evident between the paired isolates. Compared with their corresponding polymyxin-susceptible isolates, the levels of metabolites in amino sugar metabolism (UDP-N-acetyl-α-d-glucosamine and UDP-N-α-acetyl-d-mannosaminuronate) and central carbon metabolism (e.g. pentose phosphate pathway and tricarboxylic acid cycle) were significantly reduced in all polymyxin-resistant isolates [fold change (FC) > 1.5, P < 0.05]. Similarly, nucleotides, amino acids and key metabolites in glycerophospholipid metabolism, namely sn-glycerol-3-phosphate and sn-glycero-3-phosphoethanolamine, were significantly reduced across all polymyxin-resistant isolates (FC > 1.5, P < 0.05) compared with polymyxin-susceptible isolates. However, higher glycerophospholipid levels were evident in polymyxin-resistant ATH 8 and ATH 16 (FC > 1.5, P < 0.05) compared with their corresponding susceptible isolates. Conclusions To our knowledge, this study is the first to reveal significant metabolic perturbations associated with polymyxin resistance in K. pneumoniae.
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Moffatt, Jennifer H., Marina Harper, Paul Harrison, John D. F. Hale, Evgeny Vinogradov, Torsten Seemann, Rebekah Henry, et al. "Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production." Antimicrobial Agents and Chemotherapy 54, no. 12 (September 20, 2010): 4971–77. http://dx.doi.org/10.1128/aac.00834-10.
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ABSTRACT Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram-negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram-negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin-resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium.
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Malott, Rebecca J., Chia-Hung Wu, Tracy D. Lee, Trevor J. Hird, Nathan F. Dalleska, James E. A. Zlosnik, Dianne K. Newman, and David P. Speert. "Fosmidomycin Decreases Membrane Hopanoids and Potentiates the Effects of Colistin on Burkholderia multivorans Clinical Isolates." Antimicrobial Agents and Chemotherapy 58, no. 9 (June 23, 2014): 5211–19. http://dx.doi.org/10.1128/aac.02705-14.
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ABSTRACTBurkholderia cepaciacomplex (Bcc) pulmonary infections in people living with cystic fibrosis (CF) are difficult to treat because of the extreme intrinsic resistance of most isolates to a broad range of antimicrobials. Fosmidomycin is an antibacterial and antiparasitic agent that disrupts the isoprenoid biosynthesis pathway, a precursor to hopanoid biosynthesis. Hopanoids are involved in membrane stability and contribute to polymyxin resistance in Bcc bacteria. Checkerboard MIC assays determined that although isolates of the Bcc speciesB. multivoranswere highly resistant to treatment with fosmidomycin or colistin (polymyxin E), antimicrobial synergy was observed in certain isolates when the antimicrobials were used in combination. Treatment with fosmidomycin decreased the MIC of colistin for isolates as much as 64-fold to as low as 8 μg/ml, a concentration achievable with colistin inhalation therapy. A liquid chromatography-tandem mass spectrometry technique was developed for the accurate quantitative determination of underivatized hopanoids in total lipid extracts, and bacteriohopanetetrol cyclitol ether (BHT-CE) was found to be the dominant hopanoid made byB. multivorans. The amount of BHT-CE made was significantly reduced upon fosmidomycin treatment of the bacteria. Uptake assays with 1-N-phenylnaphthylamine were used to determine that dual treatment with fosmidomycin and colistin increases membrane permeability, while binding assays with boron-dipyrromethene-conjugated polymyxin B illustrated that the addition of fosmidomycin had no impact on polymyxin binding. This work indicates that pharmacological suppression of membrane hopanoids with fosmidomycin treatment can increase the susceptibility of certain clinicalB. multivoransisolates to colistin, an agent currently in use to treat pulmonary infections in CF patients.
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McConville, Thomas, Marla Giddins, Nenad Macesic, and Anne-Catrin Uhlemann. "707. Clarifying the Role of CrrB in Polymxyin-resistant Klebsiella pneumoniae Clinical Isolates Utilizing a Novel CRISPR-Cas9 System." Open Forum Infectious Diseases 5, suppl_1 (November 2018): S254—S255. http://dx.doi.org/10.1093/ofid/ofy210.714.
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Abstract Background Polymyxin resistance (PR) threatens the mainstay of therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections. While mgrB disruption accounts for most cases of PR, missense mutations in crrB have been proposed as an alternative pathway for PR through PmrA/B/C upregulation of the pmrHFIJKLM operon. It remains unknown if CrrB acts as a positive or negative regulator on its downstream targets. Methods We assembled a CRISPR-Cas9 system for gene knockouts (KO) in CRE K. pneumoniae (CRKP) using zeocin as a selectable marker. We chose a polymyxin susceptible (PS) and a PR isolate with a missense mutation in crrB (L87V) (NR5337 and NR5083, respectively) for KO. Isolates were transformed with a crrB KO plasmid, grown with zeocin selection, induced with arabinose, and plated on low-salt LB-zeocin/arabinose. KOs were confirmed via PCR and Sanger sequencing. Polymyxin susceptibility was performed with broth-microdilution. Gene expression was determined by qRT-PCR of cDNA extracts. Results Colistin MIC following crrB KO of NR5337 (PS) remained unchanged. In contrast, crrB KO of NR5083 (PR), decreased polymyxin MIC (MIC >128 to 1.0 μg/mL). qRT-PCR of NR5083 did not show increased expression of pmrA/C, nor pmrK. NR5083 ^crrB showed a small decrease in phoQ expression, compared with NR5083, but similar expression of phoP, pmrA/C and pmrK (Table 1). Conclusion Polymyxin MIC decreased >128 fold after crrB KO in a PR isolate, but colistin MIC remained unchanged after KO in a PS isolate. CrrB mutations in PR isolates may confer a gain of function with CrrB acting as a positive regulator on its downstream targets. Contrary to previous literature, no upregulation of pmrA/C and pmrHFIJKLM was detected. Differences in crrB mutations or clonal background may explain this finding. CRISPR-Cas9 may serve as a reliable system for genetic manipulation of CRKP. Further data on the impact of individual crrB missense mutations are needed. Disclosures A. C. Uhlemann, Merck: Investigator, Grant recipient.
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Lin, Quei Yen, Yi-Lin Tsai, Ming-Che Liu, Wei-Cheng Lin, Po-Ren Hsueh, and Shwu-Jen Liaw. "Serratia marcescensarn, a PhoP-Regulated Locus Necessary for Polymyxin B Resistance." Antimicrobial Agents and Chemotherapy 58, no. 9 (June 23, 2014): 5181–90. http://dx.doi.org/10.1128/aac.00013-14.
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ABSTRACTPolymyxins, which are increasingly being used to treat infections caused by multidrug-resistant bacteria, perform poorly againstSerratia marcescens. To investigate the underlying mechanisms, Tn5mutagenesis was performed and two mutants exhibiting increased polymyxin B (PB) susceptibility were isolated. The mutants were found to have Tn5inserted into thearnBandarnCgenes. In other bacteria,arnBandarnCbelong to the seven-genearnoperon, which is involved in lipopolysaccharide (LPS) modification. LPSs ofarnmutants had greater PB-binding abilities than that of wild-type LPS. Further, we identified PhoP, a bacterial two-component response regulator, as a regulator of PB susceptibility inS. marcescens. By the reporter assay, we found PB- and low-Mg2+-induced expression ofphoPandarnin the wild-type strain but not in thephoPmutant. Complementation of thephoPmutant with the full-lengthphoPgene restored the PB MIC and induction by PB and low Mg2+levels, as in the wild type. An electrophoretic mobility shift assay (EMSA) further demonstrated that PhoP bound directly to thearnpromoter. The PB challenge test confirmed that pretreatment with PB and low Mg2+levels protectedS. marcescensfrom a PB challenge in the wild-type strain but not in thephoPmutant. Real-time reverse transcriptase-PCR also indicated that PB serves as a signal to regulate expression ofugd, a gene required for LPS modification, inS. marcescensthrough a PhoP-dependent pathway. Finally, we found that PB-resistant clinical isolates displayed greater expression ofarnAupon exposure to PB than did susceptible isolates. This is the first report to describe the role ofS. marcescensarnin PB resistance and its modulation by PB and Mg2+through the PhoP protein.
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Hussein, Maytham, Rafah Allobawi, Irini Levou, Mark A. T. Blaskovich, Gauri G. Rao, Jian Li, and Tony Velkov. "Mechanisms Underlying Synergistic Killing of Polymyxin B in Combination with Cannabidiol against Acinetobacter baumannii: A Metabolomic Study." Pharmaceutics 14, no. 4 (April 3, 2022): 786. http://dx.doi.org/10.3390/pharmaceutics14040786.
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Polymyxins have resurged as the last-resort antibiotics against multidrug-resistant Acinetobacter baumannii. As reports of polymyxin resistance in A. baumannii with monotherapy have become increasingly common, combination therapy is usually the only remaining treatment option. A novel and effective strategy is to combine polymyxins with non-antibiotic drugs. This study aimed to investigate, using untargeted metabolomics, the mechanisms of antibacterial killing synergy of the combination of polymyxin B with a synthetic cannabidiol against A. baumannii ATCC 19606. The antibacterial synergy of the combination against a panel of Gram-negative pathogens (Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa) was also explored using checkerboard and static time-kill assays. The polymyxin B–cannabidiol combination showed synergistic antibacterial activity in checkerboard and static time-kill assays against both polymyxin-susceptible and polymyxin-resistant isolates. The metabolomics study at 1 h demonstrated that polymyxin B monotherapy and the combination (to the greatest extent) significantly perturbed the complex interrelated metabolic pathways involved in the bacterial cell envelope biogenesis (amino sugar and nucleotide sugar metabolism, peptidoglycan, and lipopolysaccharide (LPS) biosynthesis), nucleotides (purine and pyrimidine metabolism) and peptide metabolism; notably, these pathways are key regulators of bacterial DNA and RNA biosynthesis. Intriguingly, the combination caused a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids) compared to very minimal changes induced by monotherapies. At 4 h, polymyxin B–cannabidiol induced more pronounced effects on the abovementioned pathways compared to the minimal impact of monotherapies. This metabolomics study for the first time showed that in disorganization of the bacterial envelope formation, the DNA and RNA biosynthetic pathways were the most likely molecular mechanisms for the synergy of the combination. The study suggests the possibility of cannabidiol repositioning, in combination with polymyxins, for treatment of MDR polymyxin-resistant Gram-negative infections.
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Wang, Won-Bo, I.-Chun Chen, Sin-Sien Jiang, Hui-Ru Chen, Chia-Yu Hsu, Po-Ren Hsueh, Wei-Bin Hsu, and Shwu-Jen Liaw. "Role of RppA in the Regulation of Polymyxin B Susceptibility, Swarming, and Virulence Factor Expression in Proteus mirabilis." Infection and Immunity 76, no. 5 (March 3, 2008): 2051–62. http://dx.doi.org/10.1128/iai.01557-07.
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ABSTRACT Proteus mirabilis, a human pathogen that frequently causes urinary tract infections, is intrinsically highly resistant to cationic antimicrobial peptides, such as polymyxin B (PB). To explore the mechanisms underlying P. mirabilis resistance to PB, a mutant which displayed increased (>160-fold) sensitivity to PB was identified by transposon mutagenesis. This mutant was found to have Tn5 inserted into a novel gene, rppA. Sequence analysis indicated that rppA may encode a response regulator of the two-component system and is located upstream of the rppB gene, which may encode a membrane sensor kinase. An rppA knockout mutant of P. mirabilis had an altered lipopolysaccharide (LPS) profile. The LPS purified from the rppA knockout mutant could bind more PB than the LPS purified from the wild type. These properties of the rppA knockout mutant may contribute to its PB-sensitive phenotype. The rppA knockout mutant exhibited greater swarming motility and cytotoxic activity and expressed higher levels of flagellin and hemolysin than the wild type, suggesting that RppA negatively regulates swarming, hemolysin expression, and cytotoxic activity in P. mirabilis. PB could modulate LPS synthesis and modification, swarming, hemolysin expression, and cytotoxic activity in P. mirabilis through an RppA-dependent pathway, suggesting that PB could serve as a signal to regulate RppA activity. Finally, we demonstrated that the expression of rppA was up-regulated by a low concentration of PB and down-regulated by a high concentration of Mg2+. Together, these data highlight the essential role of RppA in regulating PB susceptibility and virulence functions in P. mirabilis.
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Ayoub Moubareck, Carole. "Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance." Membranes 10, no. 8 (August 8, 2020): 181. http://dx.doi.org/10.3390/membranes10080181.
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Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.
Dissertations / Theses on the topic "Polymyxin Resistant Pathway"
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Gatzeva-Topalova, Petia Z. "Biophysical and biochemical characterization of ArnA: A required enzyme in the polymyxin resistance pathway." Diss., Connect to online resource, 2005. http://wwwlib.umi.com/cr/colorado/fullcit?p3190368.
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Safdari, Haaris Ahsan. "Structural Characterization of Biological Macromolecules by Random Conical Tilt Pair Experiments." Thesis, 2019. https://etd.iisc.ac.in/handle/2005/4289.
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Structural biology deals with determining the structure of biological macromolecules
especially proteins, DNA, RNA. The conformational changes in the structure of a
macromolecule helps to decipher its function. This finally paves the way for structure-based
drug designing and mutational studies to assess key residues involved in the macromolecule.
X-ray crystallography has been the most common technique for structural elucidation since
almost last century and has contributed to almost 85 per cent of the structures deposited in
Protein Data Bank (PDB). However, crystallising proteins such as those associated with
membrane remains a major bottleneck till date though methods like lipid cubic phase (LCP)
have somewhat circumvented this. It is also important to realize that imperfect crystals
sometimes formed may not depict true physiological state of the protein in the cellular
context and hence drug design based on that may turn out to be futile. NMR (Nuclear
Magnetic Resonance) is a powerful technique to study the protein structure at atomic
resolution in solution. It has also been used to study kinetics and dynamics of the protein. The
major limitation of NMR is the size limit that it poses which is around 5-25 kDa and huge
amount of protein that it requires.
On the contrary, cryo-electron microscopy (cryo-EM) has emerged as a versatile tool for
studying structure of proteins and macromolecular complexes. Recent “resolution revolution”
has empowered cryo-EM in terms of resolution achieved due to better DED (Direct Electron
Detector) cameras, stable microscopes and new algorithms for data processing. This has
resulted in the surge of EM map deposition in the EMDB (Electron Microscopy Data Bank)
(Fig. 1). The number of depositions of EM map per year has been depicted in Fig. 2.