scholarly journals An Early Response to Environmental Stress Involves Regulation of OmpX and OmpF, Two Enterobacterial Outer Membrane Pore-Forming Proteins

2007 ◽  
Vol 51 (9) ◽  
pp. 3190-3198 ◽  
Author(s):  
Myrielle Dupont ◽  
Chloë E. James ◽  
Jacqueline Chevalier ◽  
Jean-Marie Pagès
Keyword(s):  
Outer Membrane ◽  
Early Response ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Membrane Pore ◽  
Bacterial Response ◽  
External Stresses ◽  
Resistant Strains ◽  
Pore Forming Proteins

ABSTRACT Bacterial adaptation to external stresses and toxic compounds is a key step in the emergence of multidrug-resistant strains that are a serious threat to human health. Although some of the proteins and regulators involved in antibiotic resistance mechanisms have been described, no information is available to date concerning the early bacterial response to external stresses. Here we report that the expression of ompX, encoding an outer membrane protein, is increased during early exposure to drugs or environmental stresses. At the same time, the level of ompF porin expression is noticeably affected. Because of the role of these proteins in membrane permeability, these data suggest that OmpF and OmpX are involved in the control of the penetration of antibiotics such as β-lactams and fluoroquinolones through the enterobacterial outer membrane. Consequently, the early control of ompX and ompF induced by external stresses may represent a preliminary response to antibiotics, thus triggering the initial bacterial line of defense against antibiotherapy.

scholarly journals Art-175 Is a Highly Efficient Antibacterial against Multidrug-Resistant Strains and Persisters of Pseudomonas aeruginosa

2014 ◽  
Vol 58 (7) ◽  
pp. 3774-3784 ◽  
Author(s):  
Yves Briers ◽  
Maarten Walmagh ◽  
Barbara Grymonprez ◽  
Manfred Biebl ◽  
Jean-Paul Pirnay ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Outer Membrane ◽  
Time Lapse ◽  
Bactericidal Effect ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
Chronic Infections ◽  
Content Type ◽  
Resistant Strains

ABSTRACTArtilysins constitute a novel class of efficient enzyme-based antibacterials. Specifically, they covalently combine a bacteriophage-encoded endolysin, which degrades the peptidoglycan, with a targeting peptide that transports the endolysin through the outer membrane of Gram-negative bacteria. Art-085, as well as Art-175, its optimized homolog with increased thermostability, are each composed of the sheep myeloid 29-amino acid (SMAP-29) peptide fused to the KZ144 endolysin. In contrast to KZ144, Art-085 and Art-175 pass the outer membrane and killPseudomonas aeruginosa, including multidrug-resistant strains, in a rapid and efficient (∼5 log units) manner. Time-lapse microscopy confirms that Art-175 punctures the peptidoglycan layer within 1 min, inducing a bulging membrane and complete lysis. Art-175 is highly refractory to resistance development by naturally occurring mutations. In addition, the resistance mechanisms against 21 therapeutically used antibiotics do not show cross-resistance to Art-175. Since Art-175 does not require an active metabolism for its activity, it has a superior bactericidal effect againstP. aeruginosapersisters (up to >4 log units compared to that of the untreated controls). In summary, Art-175 is a novel antibacterial that is well suited for a broad range of applications in hygiene and veterinary and human medicine, with a unique potential to target persister-driven chronic infections.

scholarly journals Evolution toward maximum transport capacity of the Ttg2 ABC system in Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Daniel Yero ◽  
Lionel Costenaro ◽  
Oscar Conchillo-Solé ◽  
Mireia Díaz-Lobo ◽  
Adrià Mayo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Outer Membrane ◽  
Gene Knockout ◽  
Multidrug Resistant ◽  
Crystallographic Structure ◽  
Intrinsic Resistance ◽  
Head Groups ◽  
Resistant Strains ◽  
System Thought

AbstractIn Pseudomonas aeruginosa, Ttg2D is the soluble periplasmic phospholipid-binding component of an ABC transport system thought to be involved in maintaining the asymmetry of the outer membrane. The crystallographic structure of Ttg2D at 2.5Å resolution reveals that this protein can bind two diacyl phospholipids. Native and denaturing mass spectrometry experiments confirm that Ttg2D binds two phospholipid molecules, which may have different head groups. Analysis of the available structures of Ttg2D orthologs allowed us to classify this protein family as a novel substrate-binding protein fold and to venture the evolutionary events that differentiated the orthologs binding one or two phospholipids. In addition, gene knockout experiments in P. aeruginosa PAO1 and multidrug-resistant strains show that disruption of this system leads to outer membrane permeabilization. This demonstrates the role of this system in low-level intrinsic resistance against certain antibiotics that use a lipid-mediated pathway to permeate through membranes.

scholarly journals Hydrophilic nanoparticles that kill bacteria while sparing mammalian cells reveal the antibiotic role of nanostructures

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yunjiang Jiang ◽  
Wan Zheng ◽  
Keith Tran ◽  
Elizabeth Kamilar ◽  
Jitender Bariwal ◽  
...  
Keyword(s):  
Polymer Brushes ◽  
Mammalian Cells ◽  
Pore Formation ◽  
Multidrug Resistant ◽  
Membrane Pore ◽  
Threshold Size ◽  
Resistant Strains ◽  
Viable Approach ◽  
Nanoparticle Sizes

AbstractTo dissect the antibiotic role of nanostructures from chemical moieties belligerent to both bacterial and mammalian cells, here we show the antimicrobial activity and cytotoxicity of nanoparticle-pinched polymer brushes (NPPBs) consisting of chemically inert silica nanospheres of systematically varied diameters covalently grafted with hydrophilic polymer brushes that are non-toxic and non-bactericidal. Assembly of the hydrophilic polymers into nanostructured NPPBs doesn’t alter their amicability with mammalian cells, but it incurs a transformation of their antimicrobial potential against bacteria, including clinical multidrug-resistant strains, that depends critically on the nanoparticle sizes. The acquired antimicrobial potency intensifies with small nanoparticles but subsides quickly with large ones. We identify a threshold size (dsilica ~ 50 nm) only beneath which NPPBs remodel bacteria-mimicking membrane into 2D columnar phase, the epitome of membrane pore formation. This study illuminates nanoengineering as a viable approach to develop nanoantibiotics that kill bacteria upon contact yet remain nontoxic when engulfed by mammalian cells.

scholarly journals 1280. In-Vitro Activity of Cefiderocol, Imipenem/Relebactam, & Ceftazidime/Avibactam in Ceftolozane/Tazobactam Resistant Strains of Multidrug Resistant Pseudomonas aeruginosa

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S655-S655
Author(s):  
Daniel Navas ◽  
Angela Charles ◽  
Amy Carr ◽  
Jose Alexander
Keyword(s):  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Vitro Activity ◽  
Clinical Isolates ◽  
Resistance Testing ◽  
Clinical Samples ◽  
In Vitro Activity ◽  
Carbapenemase Gene ◽  
Resistant Strains

Abstract Background The activity of imipenem/relebactam (I/R), ceftazidime/avibactam (CZA) and cefiderocol (FDC) were evaluated against clinical isolates of multidrug resistant (MDR) strains of P. aeruginosa which was resistant to ceftolozane/tazobactam (C/T). The recent increase of MDR P. aeruginosa strains isolated from clinical samples has prompted research and development of new antimicrobials that can withstand its multiple resistance mechanisms. C/T is an effective option for treatment of MDR P. aeruginosa in our facility with only 10% of resistance in MDR strains, but the emergence of resistance may occur due to the presence of a carbapenemase gene or an ampC mutation. Methods Antimicrobial susceptibility testing for C/T Etest® (bioMérieux, Inc.) were performed on all MDR strains initially screened by the VITEK2® (bioMérieux, Inc.). 10% (n=20) of all MDR isolates were resistant to C/T by the CLSI 2019 breakpoints. These resistant isolates were tested for presence of a carbapenemase gene using the GeneXpert CARBA-R (Cepheid®) PCR and against CZA Etest® (bioMérieux, Inc.) I/R gradient strips (Liofilchem®) and FDC broth microdilution (Thermo Scientific™ Sensititre™). Results A total of 20 clinical isolates of MDR P. aeruginosa resistant to C/T were tested following standardized CLSI protocols and techniques. All 20 isolates were screened for the presence of a carbapenemase gene (blaVIM, blaNDM, blaKPC, blaOXA-48, blaIMP). A blaVIM gene was detected in 6 (30%) out of 20 isolates. FDC demonstrated the greatest activity with 85% (n=17) of susceptible isolates (CLSI MIC <4µg/dL). CZA (CLSI MIC <8µg/dL) and I/R (FDA MIC <2µg/dL) showed 15% (n=3) and 10% (n=2) of susceptible isolates respectively. FDC was active against all 6 blaVIM isolates, where all 6 strains were resistant to CZA and I/R as expected. 3 isolates tested non-susceptible against FDC; additional characterization was not performed at this time. Conclusion Based on these results, FDC demonstrated the greatest in-vitro activity against C/T resistant strains of MDR P. aeruginosa. FDC also demonstrated activity against all 6 MDR P. aeruginosa carrying blaVIM gene. FDC is a strong option to consider on MDR P. aeruginosa strains based on a resistance testing algorithm and a cost/effective protocol. Disclosures All Authors: No reported disclosures

scholarly journals The Biology and Role of Interleukin-32 in Tuberculosis

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Wu Li ◽  
Wanyan Deng ◽  
Jianping Xie
Keyword(s):  
Multidrug Resistant ◽  
Drug Resistant ◽  
Host Molecule ◽  
Tuberculosis Control ◽  
Promising Alternative ◽  
Extensively Drug Resistant ◽  
Important Host ◽  
Resistant Strains ◽  
Drug Resistant Strains

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of morbidity and mortality globally, with nearly 10.4 million new cases of incidence and over 1.7 million deaths annually. Drug-resistant M. tuberculosis strains, especially multidrug-resistant or extensively drug-resistant strains, have further intensified the problem associated with tuberculosis control. Host-directed therapy is a promising alternative for tuberculosis control. IL-32 is increasingly recognized as an important host molecule against tuberculosis. In this review, we highlight the proinflammatory properties of IL-32 and the mode of action of IL-32 in mycobacterial infections to inspire the development of novel immunity-based countermeasures and host-directed therapies against tuberculosis.

scholarly journals Analysis of rdxA and Involvement of Additional Genes Encoding NAD(P)H Flavin Oxidoreductase (FrxA) and Ferredoxin-Like Protein (FdxB) in Metronidazole Resistance of Helicobacter pylori

2000 ◽  
Vol 44 (8) ◽  
pp. 2133-2142 ◽  
Author(s):  
Dong-Hyeon Kwon ◽  
Fouad A. K. El-Zaatari ◽  
Mototsugu Kato ◽  
Michael S. Osato ◽  
Rita Reddy ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Resistant Strain ◽  
Resistance Mechanisms ◽  
Sensitive Strain ◽  
Metronidazole Resistance ◽  
Genes Encoding ◽  
Resistant Strains ◽  
Flavin Oxidoreductase ◽  
H Pylori

ABSTRACT Metronidazole (Mtz) is a critical ingredient of modern multidrug therapies for Helicobacter pylori infection. Mtz resistance reduces the effectiveness of these combinations. Although null mutations in a rdxA gene that encodes oxygen-insensitive NAD(P)H nitroreductase was reported in Mtz-resistant H. pylori, an intact rdxA gene has also been reported in Mtz-resistant H. pylori, suggesting that additional Mtz resistance mechanisms exist in H. pylori. We explored the nature of Mtz resistance among 544 clinical H. pyloriisolates to clarify the role of rdxA inactivation in Mtz resistance and to identify another gene(s) responsible for Mtz resistance in H. pylori. Mtz resistance was present in 33% (181 of 544) of the clinical isolates. There was marked heterogeneity of resistance, with Mtz MICs ranging from 8 to ≥256 μg/ml.rdxA inactivation resulted in Mtz MICs of up to 32 μg/ml for 6 Mtz-sensitive H. pylori strains and 128 μg/ml for one Mtz-sensitive strain. Single or dual (with rdxA) inactivation of genes that encode ferredoxin-like protein (designatedfdxB) and NAD(P)H flavin oxidoreductase (frxA) also increased the MICs of Mtz for sensitive and resistant strains with low to moderate levels of Mtz resistance. fdxB inactivation resulted in a lower level of resistance than that from rdxAinactivation, whereas frxA inactivation resulted in MICs similar to those seen with rdxA inactivation. Further evidence for involvement of the frxA gene in Mtz resistance included the finding of a naturally inactivated frxA but an intact rdxA in an Mtz-resistant strain, complementation of Mtz sensitivity from an Mtz-sensitive strain to an Mtz-resistant strain or vice versa by use of naturally inactivated or functionalfrxA genes, respectively, and transformation of an Mtz-resistant Escherichia coli strain to an Mtz sensitive strain by a naturally functional frxA gene but not an inactivated frxA gene. These results are consistent with the hypothesis that null mutations in fdxB,frxA, or rdxA may be involved in Mtz resistance.

scholarly journals Global evolutionary epidemiology, phylogeography and resistome dynamics of Citrobacter species, Enterobacter hormaechei, Klebsiella variicola, and Proteeae clones: A One Health analyses

2020 ◽  
Author(s):  
John Osei Sekyere ◽  
Melese Abate Reta
Keyword(s):  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Global Risk ◽  
Global Epidemiology ◽  
Evolutionary Epidemiology ◽  
Enterobacter Hormaechei ◽  
Resistant Strains ◽  
Species Specific ◽  
Almost All ◽  
Respective Species

AbstractBackground.The global epidemiology and resistomes dynamics of multidrug-resistant Citrobacter spp., Enterobacter hormaechei, Klebsiella variicola, morganella morganii, Proteus mirabilis and Providencia spp. have not been described, despite their importance as emerging opportunistic clinical pathogens.Methods.The genomes of the above-mentioned organisms were curated from PATRIC and NCBI and used for evolutionary epidemiology, phylogeography and resistome analyses. The phylogeny trees were drawn using RAXmL and edited with Figtree. The resistomes were curated from GenBank and the phylogeography was manually mapped.Results and conclusion.Mcr-9 and other mcr variants were highly prevalent in E. hormaechei subsp. and substantial in C. freundii whilst KPC, OXA-48, NDM, IMP, VIM, TEM, OXA and SHV were abundant in global E. hormaechei subsp., Citrobacter freundii, P. mirabilis, P. stuartii and P. rettgeri clones/clades. Species-specific ampCs were highly conserved in respective species whilst fluoroquinolones, aminoglycosides, macrolides, fosfomycin, chloramphenicol, tetracycline, sulphamethoxazole and trimethoprim resistance mechanisms were abundantly enriched in almost all clades of most of the species, making them extensively and pandrug resistant; K. variicola, C. amalonaticus and C, koseri had relatively few resistance genes. Vertical and horizontal resistome transmissions as well as local and international dissemination of strains evolving from common ancestors were observed, suggesting the anthroponotic, zoonotic, and food-/water-borne infectiousness of these pathogens. There is a global risk of pandrug resistant strains escalating local and international outbreaks of antibiotic-insensitive infections, initiating the dawn of a post-antibiotic era.

scholarly journals Review of Ceftazidime-Avibactam for the Treatment of Infections Caused by Pseudomonas aeruginosa

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1126
Author(s):  
George L. Daikos ◽  
Clóvis Arns da da Cunha ◽  
Gian Maria Rossolini ◽  
Gregory G. Stone ◽  
Nathalie Baillon-Plot ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Real World Data ◽  
Serious Infections ◽  
Tract Infections ◽  
Abdominal Infections ◽  
Hospital Acquired

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes a range of serious infections that are often challenging to treat, as this pathogen can express multiple resistance mechanisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) phenotypes. Ceftazidime–avibactam is a combination antimicrobial agent comprising ceftazidime, a third-generation semisynthetic cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor. This review explores the potential role of ceftazidime–avibactam for the treatment of P. aeruginosa infections. Ceftazidime–avibactam has good in vitro activity against P. aeruginosa relative to comparator β-lactam agents and fluoroquinolones, comparable to amikacin and ceftolozane–tazobactam. In Phase 3 clinical trials, ceftazidime–avibactam has generally demonstrated similar clinical and microbiological outcomes to comparators in patients with complicated intra-abdominal infections, complicated urinary tract infections or hospital-acquired/ventilator-associated pneumonia caused by P. aeruginosa. Although real-world data are limited, favourable outcomes with ceftazidime–avibactam treatment have been reported in some patients with MDR and XDR P. aeruginosa infections. Thus, ceftazidime–avibactam may have a potentially important role in the management of serious and complicated P. aeruginosa infections, including those caused by MDR and XDR strains.

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