Dataset Information

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.

ABSTRACT: Artilysins 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 kill Pseudomonas 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 against P. aeruginosa persisters (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.

SUBMITTER: Briers Y

PROVIDER: S-EPMC4068523 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.

Briers Yves Y Walmagh Maarten M Grymonprez Barbara B Biebl Manfred M Pirnay Jean-Paul JP Defraine Valerie V Michiels Jan J Cenens William W Aertsen Abram A Miller Stefan S Lavigne Rob R

Antimicrobial agents and chemotherapy 20140421 7

Artilysins 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, ...[more]

PMID: 24752267

Similar Datasets

Project description:Objective:Drawing a growth curve of multidrug-resistant Pseudomonas aeruginosa (MDR-PA) provides a foundation for susceptibility testing. By observing in vitro antibacterial activity and ultrastructure cthanges on MDR-PA of the effective components in the drug-containing serum of rats after the administration of Fuzheng Jiedu Huayu decoction (FJHD), we evaluated the inhibition and direct destruction effect of bacteria by TCM alone or combined with antibiotics. Methods:The absorbance values of MDR-PA were determined at different detection time points, and a growth curve was drawn. After gavage with FJHD, drug-containing serum was collected from the rats. Using Imipenem/cilastatin sodium as the positive drug control, the in vitro antibacterial potency of FJHD and its drug-containing serum alone or in combination with antibiotics against MDR-PA was observed. The ultrastructural changes of MDR-PA treated by FJHD combined with antibiotics were observed by transmission electron microscopy. Results:Growth of the experimental strain manifested a lag phase in the first 1-4 h, an exponential growth phase at 5-20 h, and a plateau phase after 20 h. The best detection time during the susceptibility test was 16-20 h. The minimum inhibitory concentration (MIC) value of the FJHD extract group was 0.2 g/mL. The MIC value of the pure Imipenem/cilastatin sodium group was 16 ?g/mL. The MIC values of Imipenem/cilastatin sodium + blank serum, 0.5-, 1-, and 2-fold drug-containing serum groups were all 16 ?g/mL. The MIC values of Imipenem/cilastatin sodium + 4- and 8-fold drug-containing serum groups were both 8 ?g/mL. By observation under a transmission electron microscope, Imipenem/cilastatin sodium + 0.5-, 1-, and 2-fold drug-containing serum groups showed bacterial structural damage. The degree of bacterial destruction was more obvious and the quantity of damaged bacteria was increased in the Imipenem/cilastatin sodium + 4- and 8-fold drug-containing serum groups. Conclusion:Drawing the growth curve of the experimental strain had high application value for ensuring the accuracy of the drug sensitivity test results. TCM combined with antibiotics could enhance the antibacterial and direct destruction effect of bacteria in vitro, thereby inhibiting bacterial resistance to a certain extent.

Project description:BACKGROUND:We aimed to identify the main spreading clones, describe the resistance mechanisms associated with carbapenem- and/or multidrug-resistant P. aeruginosa and characterize patients at risk of acquiring these strains in Estonian hospitals. METHODS:Ninety-two non-duplicated carbapenem- and/or multidrug-resistant P. aeruginosa strains were collected between 27th March 2012 and 30th April 2013. Clinical data of the patients was obtained retrospectively from the medical charts. Clonal relationships of the strains were determined by whole genome sequencing and analyzed by multi-locus sequence typing. The presence of resistance genes and beta-lactamases and their origin was determined. Combined-disk method and PCR was used to evaluate carbapenemase and metallo-beta-lactamase production. RESULTS:Forty-three strains were carbapenem-resistant, 11 were multidrug-resistant and 38 were both carbapenem- and multidrug-resistant. Most strains (54%) were isolated from respiratory secretions and caused an infection (74%). Over half of the patients (57%) were???65 years old and 85% had ?1 co-morbidity; 96% had contacts with healthcare and/or had received antimicrobial treatment in the previous 90 days. Clinically relevant beta-lactamases (OXA-101, OXA-2 and GES-5) were found in 12% of strains, 27% of which were located in plasmids. No Ambler class B beta-lactamases were detected. Aminoglycoside modifying enzymes were found in 15% of the strains. OprD was defective in 13% of the strains (all with CR phenotype); carbapenem resistance triggering mutations (F170 L, W277X, S403P) were present in 29% of the strains. Ciprofloxacin resistance correlated well with mutations in topoisomerase genes gyrA (T83I, D87N) and parC (S87 L). Almost all strains (97%) with these mutations showed ciprofloxacin-resistant phenotype. Multi-locus sequence type analysis indicated high diversity at the strain level - 36 different sequence types being detected. Two sequence types (ST108 (n =?23) and ST260 (n =?18)) predominated. Whereas ST108 was associated with localized spread in one hospital and mostly carbapenem-resistant phenotype, ST260 strains occurred in all hospitals, mostly with multi-resistant phenotype and carried different resistance genotype/machinery. CONCLUSIONS:Diverse spread of local rather than international P. aeruginosa strains harboring multiple chromosomal mutations, but not plasmid-mediated Ambler class B beta-lactamases, were found in Estonian hospitals. TRIAL REGISTRATION:This trial was registered retrospectively in ClinicalTrials.gov ( NCT03343119 ).

Dataset Information

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.

Publications

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets