Glycopeptide derivatives.

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.

Mono and double modified teicoplanin aglycon derivatives on the amino acid no. 7; structure-activity relationship.

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.

Semisynthetic glycopeptides: chemistry, structure-activity relationships and prospects.

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.

[Non-natural aglycones of glycopeptide antibiotics of the vancomycin group. Synthesis and antibacterial activity]. / Neprirodnye aglikony glikopeptidnykh antibiotikov vankomicinovoi gruppy. Sintez i izuchenie antibakterial'noi aktivnosti.

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.

Antimicrobial activities of chemically modified thiazolyl peptide antibiotic MDL 62,879 (GE2270A).

MDL 62,879 (GE2270A) 1 is a new inhibitor of elongation factor-Tu (EF-Tu) and belongs to the class of thiazolyl peptide antibiotics. Controlled acid hydrolysis of 1 followed by treatment with base resulted in the lost of the two terminal amino acids and in the formation of water-soluble MDL 62,935 2. Although less active in vitro than its parent compound, 2 was able to inhibit by 50% an Escherichia coli cell-free protein synthesis system at roughly the same concentration of 1. MDL 62,935 2 was subjected to further modification at the beta-phenylserine residue. Derivatives obtained from 2 were less active in both antimicrobial (MIC) and enzymatic (IC50) assays. This suggests that beta-phenylserine plays an important role for the inhibition of EF-Tu by 1 and 2.

Semisynthetic derivatives of purpuromycin as potential topical agents for vaginal infections.

Purpuromycin (1) is an antibiotic with a broad spectrum of antimicrobial activity, encompassing bacteria, fungi, and protozoa, particularly those involved in vaginal infections. With the aim of enhancing the solubility and reducing the serum binding, a chemical program of modifications was undertaken on the natural compound, and a new interesting series of derivatives at the naphthoquinone system was synthesized and evaluated as potential topical agents for vaginal infections. In particular three semisynthetic derivatives, 7'-amino (8a), 7'-methylamino (8b), 7'-ethylamino (8c), of 7'-demethoxypurpuromycin seemed to be the most promising. They were tested for in vitro activity against three of the most important vaginal pathogens and showed activity similar to that of purpuromycin against Candida isolates while they were significantly more active against Trichomonas vaginalis and Gardnerella vaginalis, which are cultured in media containing blood or serum. This is probably due to the fact that the activity of the derivatives is less antagonized by these supplements than that of purpuromycin.

Substitution of amino acids 1 and 3 in teicoplanin aglycon: synthesis and antibacterial activity of three first non-natural dalbaheptides.

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.

Synthesis and biological evaluation of new fragments from kirromycin antibiotic.

New N-acyl derivatives of 1-N-desmethyl goldinamine were obtained from degradation of kirromycin. Periodate-oxidation of these derivatives provided new aldehydic fragments that were further elaborated. Both N-phenyl ureido and N-phthalimido derivatives of 1-N-desmethyl goldinamine are able to inhibit bacterial protein synthesis in cell-free assay and are active against whole microorganisms, although with lower potency than kirromycin. The derivatives from the aldehydic fragments are totally inactive.

Synthesis and antibacterial activity of derivatives of the glycopeptide antibiotic A-40926 and its aglycone.

Starting from the antibiotic A-40926 and the aglycone of A-40926 a series of compounds were prepared by modifying the free functionalities. Their antimicrobial activity was determined, particularly against Neisseria gonorrhoeae, against which A-40926, unlike other natural glycopeptides, is active. Improved in vivo activity was displayed by the monomethyl ester of A-40926 esterified at the carboxyl group of the N-acylamino-glucuronyl moiety.

A modification of the N-terminal amino acid in the eremomycin aglycone.

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.

Synthesis and antimicrobial activities of 4-purpuromycin derivatives.

Purpuromycin (1) is a natural antibiotic with a broad spectrum of activity encompassing bacteria, fungi and protozoa. A new series of derivatives of 1 was prepared by the modification or replacement of the C-4 hydroxyl group. The physico-chemical characteristics and the in vitro antimicrobial activity of these new semisynthetic purpuromycin derivatives are reported. Attachment of a variety of bulky groups to the C-4 hydroxyl group as well as acylation or mesylation of 1 gave derivatives with significantly reduced antifungal activity, while the antimicrobial activity of these derivatives against Gram-positive and Gram-negative bacteria was only slightly decreased. All compounds were inactive against Escherichia coli. The C-4 epimers showed different in vitro activity as compared with those having the natural configuration, particularly against fungi.

New semisynthetic glycopeptides MDL 63,246 and MDL 63,042, and other amide derivatives of antibiotic A-40,926 active against highly glycopeptide-resistant VanA enterococci.

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.

Lipophilicity of teicoplanin antibiotics as assessed by reversed phase high-performance liquid chromatography: quantitative structure-property and structure-activity relationships.

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.

Amides of de-acetylglucosaminyl-deoxy teicoplanin active against highly glycopeptide-resistant enterococci. Synthesis and antibacterial activity.

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.

Chemical modifications of the antibiotic purpuromycin.

Purpuromycin, isolated in our laboratories from the culture broth of Actinoplanes ianthinogenes, is very active in vitro against Gram-positive bacteria and fungi and shows variable activity against Gram-negative bacteria. Its poor bioavailability, probably due to its insolubility in aqueous media at physiological pH's, and the fact that its activity is antagonized by serum, led us to plan a chemical program with the aim of understanding the relevance of the substituents for the antibiotic activity. The original 7-methoxycarbonyl group was transformed into more hydrophilic groups by hydrolysis, by reduction and by ammonolysis or in esters with different degree of lipophilicity and steric hindrance. Almost all of the derivatives retained activity against Gram-positive bacteria but lost activity against Escherichia coli and Trichophyton mentagrophytes. Like purpuromycin, all of the derivatives show a reduced activity in the presence of serum.

N63-carboxamides of N15-alkyl and N15,N15-dialkyl derivatives of teicoplanin and deglucoteicoplanin.

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.

Octapeptide derivatives of teicoplanin antibiotics.

A series of octapeptide derivatives of teicoplanin-A2 component 2 (CTA/2), its aglycone (TD), and the L-lysyl derivatives of an amide of CTA/2 and TD, were prepared by condensation of the terminal amino group with N-hydroxysuccinimidyl esters of tert-butyloxycarbonyl (BOC) L- and D-amino acids, followed by acidic (TFA) removal of the BOC protecting function. The antimicrobial properties of these compounds were compared with those of the corresponding unmodified antibiotics and their N15-acetyl derivatives. The most active derivatives were the octapeptides with N-terminal glycine or lysine whose in vitro activity was comparable to that of the parent teicoplanins. The glycinyl and lysyl derivatives of CTA/2 showed better activity than CTA/2 against clinical isolates of Staphylococcus epidermidis and S. haemolyticus for which teicoplanin MICs were relatively high. No significant difference in their antibacterial activity was observed between octapeptides containing L- or D-lysine.

Isolation, structure determination and biological activity of A-16686 factors A' 1, A' 2 and A' 3 glycolipodepsipeptide antibiotics.

When Actinoplanes strain ATCC 33076, the producer of A-16686 A1, A2 and A3 complex, is fermented in a suitable medium three additional factors, designated A' 1, A' 2 and A' 3 are produced. These were isolated and characterized, and were shown to differ from the parent components of the original complex by lacking one mannose unit. Bioconversion of A factors into A' factors was achieved by incubation with the mycelium of Actinoplanes ATCC 33076. Factor A' 2 has better antibacterial activity than A2 against some bacteria.