In vitro antimicrobial activity of a new antibiotic, MDL 62,879 (GE2270 A) (original) (raw)
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Antimicrobial activity of MDL 63,246, a new semisynthetic glycopeptide antibiotic
Antimicrobial agents …, 1995
MDL 63,246 is a semisynthetic derivative of the naturally occurring glycopeptide antibiotic MDL 62,476 (A40926). It was more active in vitro against Staphylococcus aureus and coagulase-negative staphylococci than MDL 62,476, teicoplanin, and vancomycin and was more active than mideplanin (MDL 62,873) against some isolates. MDL 63,246 had excellent activity against streptococci and teicoplanin-susceptible enterococci, and it also had in vitro activity against some VanA enterococcal isolates. It was more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It was highly efficacious in reducing the bacterial load in the hearts of rats in staphylococcal endocarditis experiments and the bacterial load of Staphylococcus epidermidis in a thigh infection model in neutropenic mice. The excellent in vivo activity of MDL 63,246 appears to correlate both with its in vitro antibacterial activity and with its long half-life in rodents.
Antibiotics A21459 A and B, New Inhibitors of Bacterial Protein Synthesis. II. Structure Elucidation
The Journal of Antibiotics, 1996
The structures of the antibiotics, active against a few Gram-negative bacteria and Clostridium difficile, were determined on the basis of physicochemical analyses on the intact molecules and on the acid hydrolysate of A21459 A. FAB-MSand XHand 13C NMRinvestigations identified the amino acid units and determined their sequence. Antibiotics A21459 A and B are homodetic cyclic peptides constituted by eight amino acid units. They are glycine, methoxytryptophan, tryptophan, cysteine, alanine, sarcosine, dehydroalanine, and a-aminobutyric acid for A21459 A (alanine for A21459 B). Cysteine and alanine condensed to form a thiazole moiety, according to the biosynthesis of thiazole containing antibiotics.
Antibiotic GE37468 A: A Novel Inhibitor of Bacterial Protein Synthesis. II. Structure Elucidation
The Journal of Antibiotics, 1995
GE2270 A, produced by Planobispora rosea ATCC53773, inhibits Gram-positive bacteria and anaerobes by acting on the bacterial protein synthesis. The structure has been determined by physico-chemical methods applied to the intact molecule and to the main hydrolysis products. Characterization by UV, IR, NMR(double quantum filter COSY), acid-base ionization, elemental analysis and FAB-MSindicated that GE2270 A is a highly modified peptide having MW1,289 and formula C56H55N15O10S6, and a weak basic function, and that it belongs to the thiazolyl peptide group of antibiotics. Acid hydrolysis yielded a main product (MW634), responsible for the chromophoric absorption, and a number of hydrolyzed products of lower MW. 13C NMRinverse techniques and MSstudies (El, positive ion chemical ionization, and collision induced dissociation FAB-MS-MSexperiments) on GE2270 A, the chromophoric compound, and the other hydrolysis products led to the complete identification of the various amino acid residues and their sequence. Two out of the six chiral centers have been determined. The structure is thought to originate from modification ofa chain of 14 amino acids in a process which creates 6 thiazole rings and one pyridine. The modification process also closes the linear polypeptide to form a cyclic part with an attached side-chain. GE2270 A plausibly has a similar biosynthetic origin to that of other thiazolyl peptide antibiotics such as nosiheptide and micrococcin. GE2270A is a new antibiotic isolated from the Planobispora rosea strain ATCC537731}. The mechanism of action of GE2270A is the specific inhibition of bacterial protein biosynthesis by acting on the elongation factor Tu (EF-Tu)1). GE2270 A was extracted with methanol from the mycelium and was purified by column chromatography on silica gel. After purification it is obtained as a white powder. GE2270 A is active in vitro against Gram-positive and a few Gram-negative bacteria. It is particularly active against anaerobes1*. Experimental The UVabsorption spectra were recorded with a Perkin-Elmer spectrophotometer model 320 in methanol solutions as such and at the extreme pH values obtained by adding a trace of HC1 or KOH. The IR absorption spectra were obtained from a mineral oil suspension and in chloroform solution with a Perkin-Elmer spectrophotometer model 580. The acid-base titrations in aqueous medium were obtained with 0.1 n KOHor with 0.1 N HC1on a
New antibiotic that acts specifically on the GTP-bound form of elongation factor Tu
The EMBO Journal, 1991
Communicated by A.Bernardi The new thiazolyl peptide antibiotic GE2270 A, isolated from Planobispora rosea strain ATCC 53773, is shown to inhibit bacterial protein biosynthesis in vitro by affecting specifically the GTP-bound form of elongation factor Tu (EF-Tu). The 'off' rate of EF-Tu GTP is slowed down 400-fold, locking GTP on EF-Tu, whereas EF-Tu GDP is unaffected. Therefore, on the EF-Tu guanine nucleotide interaction, GE2270 A mimicks the effect of aa-tRNA. In line with this, the binding of aa-tRNA to EF-Tu GTP is hindered by the antibiotic, as shown by the absence of a stable ternary complex and the inhibition of the enzymatic binding of aa-tRNA to the ribosome. This blocks the elongation cycle. GE2270 A does not essentially modify the intrinsic GTPase activity of EF-Tu, but impairs the stimulation by ribosomes of this reaction. The negative effect of GE2270 A on the EF-Tu GTP interaction with aa-tRNA bears similarities with that of the structurally unrelated pulvomycin, whereas marked differences were found by comparing the effects of these two antibiotics on EF-Tu GDP. This work emphasizes the varieties of the transitional conformations which tune the EF-Tu interaction with GTP and GDP.
In vitro antimicrobial activity of a novel compound, Mul-1867, against clinically important bacteria
Antimicrobial Resistance and Infection Control, 2015
Background: The antimicrobial activity of Mul-1867, a novel synthetic compound, was tested against 18 bacterial strains, including clinical isolates and reference strains from culture collections. Methods: The minimal inhibitory concentration (MICs) and minimal bactericidal concentration (MBCs) were determined by using the broth macrodilution method. The kinetics of the inhibitory effects of Mul-1867 against biofilm-growing microorganisms was assessed at time-kill test in vitro against 48-hold biofilms of Staphylococcus aureus and Escherichia coli. Transmission electron microscopy analyses was conducted to examine cell disruption. Results: A comparative assessment of the antimicrobial activities of Mul-1867 and chlorhexidine digluconate (CHG), used as a control antimicrobial, indicated that Mul-1867 was significantly more effective as a disinfectant than CHG. Mul-1867 showed potent antimicrobial activities against all the tested bacteria (MIC: 0.03-0.5 μg/mL). Furthermore, MBC/MIC ratio of Mul-1867 for all tested strains was less than or equal to 4. Time-kill studies showed that treatment with Mul-1867 (0.05-2 %) reduced bacterial numbers by 2.8-4.8 log10 colony forming units (CFU)/mL within 15-60 s. Bactericidal activity of Mul-1867 was confirmed by morphological changes revealed by TEM suggested that the killing of bacteria was the result of membrane disruption. Conclusion: Overall, these data indicated that Mul-1867 may be a promising antimicrobial for the treatment and prevention of human infections.
New antimicrobial peptide active against Gram-positive pathogens
The Indian journal of medical research, 2004
Human and animal cystatins have been shown to inhibit the replication of certain viruses and bacteria, though it is not directly demonstrated that the effects are due to protease inhibitory capacity of the cystatins. We report antibacterial properties of a novel antimicrobial peptidyl derivative, (2S)-2-(N(alpha)-benzyloxycarbonyl-arginyl-leucylamido)-1-[(E)-cinnamoylamido]-3- methylbutane, structurally based upon the aminoterminal segment of the inhibitory centre of the human cysteine protease inhibitor, cystatin C. Clinical isolates of group A, B, C and G streptococci were collected. The antibacterial activity of Cystapep 1 derivative was tested by agar well diffusion method. Cystapep 1, displayed antibacterial activity against several clinically important Gram-positive bacteria. It displayed minimal inhibitory and bactericidal concentrations of about 16 microg/ml for both Staphylococcus aureus and Streptococcus pyogenes. In radial agar diffusion assays, groups A, B, C and G strep...
bioRxiv (Cold Spring Harbor Laboratory), 2022
Objectives Multidrug-resistant (MDR) bacteria are a continuously increasing threat for medicine, causing infections recalcitrant to antibiotics. Antimicrobial peptides (AMPs) were identified as alternatives to antibiotics, being naturally occurring short peptides and part of the innate immune system of a vast majority of organisms. However, the clinical application of AMPs is limited by suboptimal pharmacokinetic properties and relatively high toxicity. Combinatorial treatments using AMPs and classical antibiotics may decrease the concentrations of AMPs required for bacterial eradication, thus lowering the side effects of these peptides. Methods Here, we investigate the in vitro efficiency of combinations of the recently described antimicrobial peptide TAT-RasGAP317-326 with a panel of commonly used antimicrobial agents against three Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii using checkerboard and time-kill assays. Results We identified synergistic combinations towards all three bacteria and demonstrated that these combinations had an increased bactericidal effect compared to individual drugs. Moreover, combinations were also effective against clinical isolates of A. baumannii. Finally, combination of TAT-RasGAP317-326 and meropenem had a promising antibiofilm effect towards A. baumannii. Conclusion Taken together, our results indicate that combinations of TAT-RasGAP317-326 with commonlyused antimicrobial agents may lead to the development of new treatment protocols against infections caused by MDR bacteria.
Update of peptides with antibacterial activity
For many years a battle has been going on between bacteria and humans, with bacteria trying to survive against the antibiotics used by humans. Bacteria are found to be dominant in this battle since they can develop resistance. In fact, in the last decade multi-, extended-and pan-drug resistant bacteria have been isolated. On the other hand, the number of new antibiotics approved by the FDA has dramatically decreased during the last 20 years. Therefore, there is a desperate need for developing new types of antibacterial agents, where antimicrobial peptides may play an important role. This review provides an update of the recently identified antimicrobial peptides. Three valid approaches for developing a future antibacterial agent, as are the mechanisms of action as well as the in vitro and in vivo assays have been described in depth. In comparison to the antibacterial agents available at present, the targets for most of the antimicrobial peptides are not well known. However several proposals having been introduced for many antimicrobial peptides of different mechanisms of action, there still lies some uncertainty about their utility. Hundreds of antimicrobial peptides have been tested in vitro against all types of bacteria, but in this review we will highlight only those which have been tested against the most important Grampositive and Gram-negative bacteria. The last step to get a potential antibiotic includes studies with an in vivo model. Therefore only antimicrobial peptides with good activity are tested that have been described in this review.
Assessment of Antibacterial Activity of Smaller Chain Tripeptides and Tetrapeptides
Our objective is to investigate the smaller chain tripeptides and tetrapeptides with the efforts mainly directed towards the identifi cation of compounds presenting a high bactericidal activity. In this connection, 5 peptides, Met- Arg-Tyr (MRY), Met-Val-Tyr (MVY), Met-Ile-Cys-Tyr (MICY), Phe-Trp-Lys-Tyr (FWKY) and Met-Trp-Lys-Tyr (MWKY) were synthesized by solid phase peptide synthesis. The column eluted pure synthesized compounds were tested for in-vitro antibacterial disc diff usion assay using 2 g positive S. aureus , B.subtilis and 1 g negative E.coli bacterial strains at different concentrations predicted by pH and inhibitory concentration fi dings. 2 of the tetrapeptides, Phe-Trp-Lys- Tyr (FWKY) and Met-Trp-Lys-Tyr (MWKY) were found to be highly effi cient against all the gram positive and microbial strains tested. Maximum activity was observed at a concentration of 300 μg/ml (499.17 μM) for the tetrapeptide Phe-Trp-Lys-Tyr (FWKY) against B. subtilis and at a concentration of 450 μg/ml (748.75 μM) against E. coli with the corresponding zonal inhibition diameter readings (17 mm; 16 mm). The tetrapeptide Met-Trp-Lys-Tyr (MWKY) was found to have high potency against S. aureus at a concentration of 450 μg/ml (769.23 μM) with the corresponding zonal inhibition diameter as 13 mm. The experimental results are analysed statistically by t-test at 5 % and 1 % level of signifi cance. Our tetrapeptides have shown antibacterial action against both gram positive and gram negative strains and are considered safer as par with commercial antibiotics available today. Further clinical studies will make sure to position our potent small chain tetrapeptides in the arsenal of new broad spectrum anti-gram positive and anti-gram negative agent