ABSTRACT
Resistance to glycopeptides in enterococci, which first emerged in the late 1980's and is now widespread mainly in the United States, is posing a serious clinical problem due to the lack of alternative and efficacious therapeutic options, particularly against infections caused by VanA strains that are highly resistant to glycopeptides and almost all other antibiotics. In addition, isolates of Staphylococcus aureus, known as GISA, that are poorly susceptible to vancomycin and teicoplanin have been identified. Thus, there is an urgent need to develop new and more potent glycopeptides that are active against these problematic organisms. The following review will focus on the development of second-generation glycopeptides, namely LY333328 (Eli Lilly) and BI 397 (Biosearch Italia, in license to Versicor for North America), which are currently undergoing clinical trials in humans for their promising activity against VanA enterococci (LY333328), staphylococci (BI 397), and penicillin-resistant pneumococci. Both compounds were identified as the result of chemical programs that were aimed at pursuing activity of vancomycin-like or teicoplanin-like natural glycopeptides against VanA enterococci and multidrug-resistant staphylococci. More recent approaches toward glycopeptides modified in their heptapeptide core are also described. These include compounds in which amino acids 1 and 3 are replaced with other amino acid moieties such as in the modification of the asparagine side chain on residue 3 as well as attempts to change the structure of the heptapeptide backbone in positions that are critical for the molecular interaction with susceptible D-Ala-D-Ala and resistant D-Ala-D-Lactate targets. Covalently linked glycopeptide dimers and vancomycin derivatives in which vancosamine is suitably replaced with other sugar moieties will also be covered.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Amino Acid Substitution , Animals , Bacterial Proteins/drug effects , Binding Sites , Carbon-Oxygen Ligases/drug effects , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial , Enterococcus/drug effects , Glycopeptides , Lipoglycopeptides , Structure-Activity Relationship , Teicoplanin/analogs & derivatives , Vancomycin/chemistrySubject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Glycopeptides , Alkylation , Anti-Bacterial Agents/chemistry , Enterococcus faecalis/drug effects , Enterococcus faecium/drug effects , Magnetic Resonance Spectroscopy , Mass Spectrometry , Microbial Sensitivity Tests , Molecular Structure , Staphylococcus/drug effects , Teicoplanin/analogs & derivativesABSTRACT
A series of 7d-aminomethylated derivatives (mono modified) and their amides (double modified) at the amino acid No. 7 of teicoplanin aglycon were prepared with the aim of obtaining activity against vancomycin-resistant VanA enterococci. Among mono modified compounds, the 7d-n-decylaminomethyl derivative was the most active against VanA enterococci (4 micrograms/ml). Amides of the latter with 3-dimethylamino-propylamine or methylamine were found to be up to four times more active against glycopeptide-susceptible Gram-positive bacteria, and up to four times less active against VanA enterococci than the starting compound.
Subject(s)
Anti-Bacterial Agents , Teicoplanin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Staphylococcus/drug effects , Streptococcus/drug effects , Structure-Activity Relationship , Teicoplanin/chemistry , Teicoplanin/pharmacologyABSTRACT
A new approach for the modification of the heptapeptide core of glycopeptide antibiotics was proposed based on the replacement of amino acid residues in positions 1 and 3 in teicoplanin aglycone and in position 1 in the eremomycin aglycone. Six novel nonnatural aglycones of the vancomycin type were obtained. Compounds derived from the teicoplanin aglycone exhibited in vitro activity against Gram-positive bacteria, and two of them were also active against the vancomycin-resistant enterococci.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Vancomycin/analogs & derivatives , Vancomycin/pharmacology , Vancomycin/chemistryABSTRACT
Glycopeptides are a class of naturally occurring antibiotics produced by fermentation of microorganisms. They inhibit cell wall biosynthesis in bacteria by forming a complex with the C-terminal D-alanyl-D-alanine of growing peptidoglycan chains. Glycopeptides are active against Gram-positive bacteria including the major pathogens. Among all the glycopeptides that have been discovered, only vancomycin and teicoplanin are on the market for the clinical use. By modification of the natural glycopeptide it is possible to increase its activity against methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. Basic amides of teicoplanin aglycon have produced one compound endowed with interesting activity against Gram-negative bacteria because of its ability to cross the outer membrane of this last bacteria. Selective degradation of teicoplanin has given a tetrapeptide, a key intermediate that has been used as starting material for the synthesis of new non natural glycopeptides. One of them has shown a weak but promising activity against Van A Enterococci highly resistant to natural glycopeptides.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Glycopeptides , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Binding Sites , Structure-Activity RelationshipABSTRACT
The replacement of amino acids 1 and 3 of glycopeptide antibiotics (dalbaheptides) with new amino acids or other chemical entities suitable to interact with both glycopeptide-resistant (D-Ala-D-Lactate) and susceptible (D-Ala-D-Ala) targets is one of the chemical strategies currently followed to pursue activity against highly glycopeptide-resistant VanA enterococci while maintaining activity against glycopeptide-susceptible Gram-positive bacteria, particularly methicillin-resistant staphylococci. As a preliminary approach, the substitution of amino acid 1 of deglucoteicoplanin (TD) with D-lysine or D-methylleucine and of its amino acid 3 with L-phenylalanine or L-lysine was investigated. In this paper, the synthesis and in vitro antibacterial activities of first non-natural dalbaheptide methyl ester aglycons MDL 63,166 (D-Lys1-Phe-3-TD-DHP-Me), MDL 64,945 (D-Lys1-Lys3-TD-DHP-Me), and MDL 64,468 (D-MeLeu1-Lys3-TD-DHP-Me) are described. These compounds, which were obtained from intermediate TD-derived tetrapeptide methyl ester (TDTP-Me) according to a 9-step overall procedure, had excellent anti-staphylococcal activity. The most active derivative against staphylococci, MDL 64,945 (MIC: 0.063 microgram/ml for S. aureus, S. epidermidis and S. haemolyticus) was inactive against VanA enterococci, while MDL 63,166 and MDL 64,468 were somewhat active against VanA strains of E. faecalis; MDL 64,468 was also moderately active against one VanA isolate of E. faecium and had marginal activity as TD against E. coli.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Glycopeptides , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Structure-Activity RelationshipABSTRACT
An Edman degradation of the antibiotic eremomycin aglycone produced the corresponding hexapeptide, which was aminoacylated with D-lysine, D-histidine or D-tryptophan derivatives to give new heptapeptide analogs of the eremomycin aglycone. The aminoacylation of the eremomycin aglycone produced an octapeptide analog. The substitution of D-lysine for the N-terminal N-methyl-D-leucine does not seriously affect the in vitro antibacterial properties of the eremomycin aglycone whereas the heptapeptides with the N-terminal D-tryptophan or D-histidine moieties and the octapeptide with the N-terminal D-lysine are practically devoid of the antibacterial properties.
Subject(s)
Anti-Bacterial Agents/chemistry , Antimicrobial Cationic Peptides , Peptides/chemistry , Peptides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Glycopeptides , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A series of amide derivatives of natural glycopeptide A-40,926 (A), its 6B-methyl ester (MA) and 6B-decarboxy-6B-hydroxymethyl derivative (RA) were prepared with the aim of obtaining activity against glycopeptide-resistant enterococci. These compounds are structurally related to a class of amides of 34-de(acetylglucosaminyl)-34-deoxy teicoplanin which showed interesting activity against strains of Enterococcus faecalis and E. faecium highly resistant to both vancomycin and teicoplanin. Among them, RA-amides MDL 63,246 and MDL 63,042 were the most active derivatives against several Gram-positive bacteria, including VanB and VanC enterococci, and were moderately active (MIC range 0.5 approximately 64 micrograms/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICs were > or = 128 micrograms/ml. The chemical rationale and the synthesis of these new series of glycopeptide derivatives are described. Preliminary in vitro data are reported and structure-activity relationships are discussed.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Chromatography, High Pressure Liquid , Drug Resistance, Microbial , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Teicoplanin/analogs & derivatives , Teicoplanin/chemical synthesis , Teicoplanin/chemistry , Teicoplanin/pharmacology , Vancomycin/pharmacologyABSTRACT
Removal, by selective reduction, of the acetylglucosamine from teicoplanin A2-2 (CTA/2) produced the 34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone (II). This compound was more active in vitro than CTA/2 against coagulase-negative staphylococci (CNS). Amide derivatives obtained by condensation of the carboxyl group of II with primary amines were particularly active against Streptococcus pyogenes and had some in vitro activity against VanA enterococci highly resistant to both teicoplanin and vancomycin. Among them, a carboxamide (VII) with a branched tetramine also had better activity than the corresponding amide of teicoplanin against CNS. In contrast, the dimethylamide (VIII) of II had little activity against VanA enterococci. While the overall structure of the heptapeptide backbone of the secondary carboxamides of II is the same as in CTA/2 and its amide derivatives, in deoxy pseudoaglycone II and its tertiary amide VIII the 51,52-peptide bond undergoes a conformational change from the original cisoid to the transoid orientation. This difference between the secondary amides of II and dimethylamide VIII is reflected in their different antibacterial spectrum. The direct synthesis of the amides of deoxy pseudoaglycone II from parent CTA/2-amides by reaction with sodium borohydride is also described.
Subject(s)
Streptococcus pyogenes/drug effects , Teicoplanin/analogs & derivatives , Amides/chemistry , Drug Resistance, Microbial , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment , Teicoplanin/pharmacologyABSTRACT
Structure-lipophilicity relationships of a large series of 63-COX teicoplanin antibiotic derivatives were examined, by correlating their capacity factors (log kw), measured through reversed-phase high-performance liquid chromatography on Deltabond C8 stationary phase, with some computed molecular properties such as fragmental log P constants (pi x), molecular volumes (Vx) and factors imparting hydrophilicity (e.g. amino groups in the X chain, nN). A number of equations were derived which demonstrate that variations of log kw are mainly related to changes in bulk (modelled by Vx) and polarity (primarily modelled by nN) of X chains of teicoplanin derivatives. QSAR analysis revealed that in-vitro activity against E. coli increases as lipophilicity decreases and isoelectric point increases.
Subject(s)
Escherichia coli/drug effects , Teicoplanin/pharmacology , Chromatography, High Pressure Liquid , In Vitro Techniques , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Reference Standards , Structure-Activity Relationship , Teicoplanin/chemistry , Teicoplanin/metabolism , Water/chemistry , Water/metabolismABSTRACT
The synthesis and biological properties of a series of N63-carboxamides of 15-N-alkylated derivatives of teicoplanin A2 (CTA) and its aglycone (TD) are described. Among the compounds, those carrying hydrophilic groups or ionizable amino functions on the N15-alkyl chain are more soluble in water than parent N15-methylated or unmodified amides. Selected compounds were more active in vitro than CTA or TD, and a few of them were also slightly more efficacious in vivo than the parent antibiotics in streptococcal septicemia in the mouse. Their degree of activity varied with the structure and length of the N15-alkyl chains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Teicoplanin/analogs & derivatives , Alkylation , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacteremia/drug therapy , Mice , Microbial Sensitivity Tests , Streptococcal Infections/drug therapy , Structure-Activity RelationshipABSTRACT
Basic carboxamides of teicoplanin A2 (CTA) and its aglycon (TD) are prepared by condensation of the 63-carboxyl function of these antibiotics with linear or branched polyamines. The antimicrobial activities of some of the resulting compounds were better than those of the unmodified antibiotics. The presence of more than one basic group in the amidic chain enhanced the in vitro activity of some TD-amides against Gram-negative bacteria; two of these derivatives were also effective in vivo against Escherichia coli septicemia in the mouse. Among the CTA derivatives, the amide with spermine showed some unexpected in vitro activity against Gram-negatives. Both CTA- and TD-amides with polyamines are very soluble in water over a wide range of pH and are very hydrophilic.
Subject(s)
Teicoplanin/analogs & derivatives , Amides/chemical synthesis , Amides/pharmacology , Amino Acid Sequence , Animals , Bacteremia/drug therapy , Escherichia coli Infections/drug therapy , Mice , Microbial Sensitivity Tests , Molecular Sequence Data , Oligopeptides/metabolism , Polyamines/chemistry , Protein Binding , Streptococcal Infections/drug therapy , Streptococcus pyogenes , Structure-Activity Relationship , Teicoplanin/chemical synthesis , Teicoplanin/pharmacologyABSTRACT
The condensation of the terminal carboxyl group of the deglucoteicoplanin (TD) with various substituted hydrazines produced hydrazide derivatives having different physico-chemical properties. This chemical modification of the carboxyl function does not affect the ability of teicoplanin antibiotics to interfere in bacterial cell-wall synthesis. The antibacterial activity of deglucoteicoplanin hydrazides (V) were found to depend mostly on their ionic character. All the hydrazides were slightly more active than TD on Escherichia coli. Those possessing an additional basic group were more in vitro active than TD against Gram-negative microorganisms. In Experimental Streptococcus pyogenes septicemia in the mouse, basic hydrazides were more active than other derivatives when administered subcutaneously although they are as potent as TD.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Hydrazines/chemical synthesis , Peptides, Cyclic/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacology , Hydrazines/chemistry , Hydrazines/pharmacology , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Sepsis/drug therapy , Streptococcal Infections/drug therapy , Streptococcus pyogenes/drug effectsABSTRACT
By combination of several 1H NMR techniques, the sequence of actagardine has been elucidated. It has been shown that it is a tetracyclic 19-residue peptide antibiotic. It differs from the previously described lanthionine-containing peptide antibiotics belonging to the lantibiotic class.
Subject(s)
Anti-Bacterial Agents/chemistry , Amino Acid Sequence , Bacteriocins , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Sequence Data , Peptides/chemistryABSTRACT
A series of basic carboxamides of actagardine (1), a lantibiotic possessing good antistreptococcal activity, were synthetized. Some physico-chemical characteristics, in particular charge and lipophilicity, that influence water solubility were determined. The in vitro and in vivo activity was evaluated. The monocarboxamides were generally more active than actagardine against selected Gram-positive bacteria. The 3,3-dimethylamino-1-propylamide hydrochloride (4) showed good water solubility, bactericidal action and favourable antibacterial activity and it appears to be a suitable drug for further investigation.
Subject(s)
Amides/chemical synthesis , Anti-Bacterial Agents , Anti-Bacterial Agents/chemical synthesis , Amides/chemistry , Amides/pharmacokinetics , Amides/pharmacology , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Bacteriocins , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Peptides/chemistry , Peptides/pharmacokinetics , Peptides/pharmacology , Sepsis/drug therapy , Solubility , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Streptococcal Infections/drug therapy , Streptococcus/drug effects , Streptococcus pyogenes/drug effectsABSTRACT
The synthesis and the biological properties of a series of N15-alkyl and N15,N15-dialkyl derivatives of teicoplanin A2, its pseudoaglycones and aglycone are described. The alkylation of the terminal amino group did not affect the ability of these teicoplanin derivatives to bind with Ac2-L-Lys-D-Ala-D-Ala, a synthetic model of the antibiotic's target peptide in bacterial cell walls, but influenced their in vitro and in vivo antimicrobial activities to a different extent, depending on the structure and length of the alkyl chains and the type and number of sugars present.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Alkylation , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Chromatography, High Pressure Liquid , Glycopeptides/chemistry , Glycopeptides/metabolism , Glycopeptides/pharmacology , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Molecular Sequence Data , Molecular Structure , Peptides/metabolism , Sepsis/drug therapy , Streptococcal Infections/drug therapy , Streptococcus pyogenes/drug effects , TeicoplaninABSTRACT
A series of peptide derivatives of teicoplanin A2 (CTA) and deglucoteicoplanin (TD) was prepared by condensation of the 63-carboxyl function with the alpha-amino group of selected amino acids and their derivatives. The modification of the ionic character of CTA and TD influenced their in vitro and in vivo antimicrobial properties to a different extent, depending on the structure of the amino acidic moiety at C-63. A certain effect on binding strength to Ac2-L-Lys-D-Ala-D-Ala, a synthetic model of the antibiotic's target peptide, was also observed.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Glycopeptides/chemical synthesis , Glycopeptides/therapeutic use , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Molecular Sequence Data , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Sepsis/drug therapy , Streptococcal Infections/drug therapy , Structure-Activity Relationship , TeicoplaninABSTRACT
Mono- and didechlorinated derivatives of the antibiotic teicoplanin, its pseudoaglycones and aglycone, and of one amide and ester of deglucoteicoplanin were prepared under selective reductive conditions. The selectivity and rate of dehalogenation were studied and compared to those of vancomycin and deglucovancomycin. The influence of the chlorine substituents on the mechanism of action and antibacterial activity of teicoplanin antibiotics was also investigated.