Antimicrobial activity of aridicins, novel glycopeptide antibiotics with high and prolonged levels in blood

112

In the course of a search for glycopeptide antibiotics having novel biological properties, we isolated A40926. Produced by an actinomycete of the genus Actinomadura, A40926 is a complex of four main factors which contain a fatty acid as part of a glycolipid attached to the peptide backbone. Its activity was, in most respects, similar to that of other glycopeptides, such as vancomycin and teicoplanin. However, in addition to inhibiting gram-positive bacteria, A40926 was very active against Neisseria gonorrhoeae. A40926 was rapidly bactericidal for N. gonorrhoeae clinical isolates at concentrations equal to or slightly higher than the MIC. In mice, levels in serum were higher and more prolonged than those of an equivalent subcutaneous dose of teicoplanin. These properties suggest that A40926 may have potential in the therapy of gonorrhea.The increased frequency of isolation of multiply antibioticresistant gram-positive bacteria has led to wider use of antibacterial agents which were originally rarely considered for first-line therapy, such as the glycopeptide vancomycin (18). One of the advantages of this antibiotic is that, thus far, resistance is rare and restricted to certain coagulase-negative staphylococci (25). The success of vancomycin has stimulated the development of new glycopeptides, such as teicoplanin (5,13,32,33). These antibiotics inhibit cell wall biosynthesis by binding to the D-alanyl-D-alanine portion of nascent peptidoglycan (22). Specific binding to an affinity resin containing acyl-D-alanyl-D-alanine groups (9) formed the basis of our search for new glycopeptides.Among the new glycopeptides identified, we focused our attention on those having novel biological properties. A40926 is the most interesting antibiotic which has emerged thus far from our screening campaign. In fermentation broths, we found it as a complex of four factors (PA, PB, A, and B). PA and PB, described here for the first time, predominated in the broth; during purification, these two compounds were largely converted to A and B, whose structures have been described recently (31a). One feature of all four factors, which relates them to teicoplanin and some other glycopeptides (aridicins and kibdellins) (3, 27, 12) while distinguishing them from vancomycin, ristocetin, and others, is the presence of a fatty acid moiety attached to one of the sugars. In terms of biological activity, the most striking difference between the components of the A40926 complex and other glycopeptide antibiotics is their activity against Neisseria gonorrhoeae.MATERIALS AND METHODS Isolation of A40926. We screened specifically for glycopeptide antibiotics by passing fermentation broths over the affinity resin Sepharose-D-alanyl-D-alanine (9) and eluting adsorbed glycopeptides with 1% aqueous ammonia. The strain producing A40926 was found in a soil sample collected in India. Batch adsorption to the same affinity resin described above yielded nearly pure A40926 complex in one step. Quick neutralization of the ammonia eluate yielded primarily the two fac...

Section: Resultsmentioning

confidence: 99%

“…Actaplanin, A35512B, A41030A, and A47934 were obtained from Eli Lilly & Co.; avoparcin was from Lederle Laboratories. Ristocetin was purchased from Sigma Chemical Co., and aridicin (14) Bactericidal activity. Inocula were at least 106 CFU/ml.…”

Section: Methodsmentioning

confidence: 99%

A40926, a new glycopeptide antibiotic with anti-Neisseria activity

Goldstein¹,

Selva²,

Gastaldo³

et al. 1987

112

“…Thus, subcutaneous administration decreased the acute apparent in vivo potency but extended the duration of action of these glycopeptides. The data obtained after subcutaneous dosing provide information on the antibiotic concentrations in serum under conditions used in mouse protection studies reported previously (6).…”

Section: Resultsmentioning

confidence: 99%

“…The results of previous prophylaxis experiments in laboratory infection studies indicate that the aridicins and their hydrolysis products have long durations of action (6). In (8).…”

mentioning

confidence: 99%

Charge and lipophilicity govern the pharmacokinetics of glycopeptide antibiotics

Pitkin¹,

Mico²,

Sitrin³

et al. 1986

Self Cite

The pharmacokinetics and urinary excretion of nine glycopeptide antibiotics with diverse pls (3.8 to 8.5) and lipophilicities were studied. The disposition of the aridicin antibiotics and their hydrolysis products were examined in male CD-1 mice after subcutaneous and intravenous administration and compared with the disposition of teicoplanin, ristocetin, and vancomycin. The total systemic clearance, half-life, volume of distribution, and urinary excretion were highly correlated with pIs. In general, as the pI decreased, the clearance, urinary recovery, and volume of distribution decreased, whereas the half-life increased. With those glycopeptides that had similar pIs, clearance decreased and half-life increased with increasing lipophiicity. The urinary recovery of the glycopeptides decreased with decreasing pI and increasing lipophilicity. Because vancomycin (pI = 8.0) is cleared by glomerular filtration, increased binding to serum is the likely mechanism of reduced renal clearance for glycopeptides with low pls. These results are consistent with previous findings concerning the correlation of physical-chemical properties and the drug disposition of small organic molecules. Results of these studies also indicate that desirable pharmacokinetic properties can be incorporated into glycopeptides through semisynthetic modifications.

“…The only difference between factors A and B is the length of their fatty acid chains (n-undecanoic acid in A, isododecanoic acid in B). The presence of a glycolipid (also found in teicoplanin and aridicins) appears to be correlated with a longer elimination half-life in animals and humans (5,7). Subcutaneously (s.c.) administered A40926 is effective in curing experimental septicemia, and preliminary data indicated that A40926 has a particularly long half-life in mice (4).…”

mentioning

confidence: 99%

Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses

Bernareggi¹,

Danese²,

Cavenaghi³

1988

). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%.A40926 is a new glycopeptide antibiotic produced by Actinomadura sp. ATCC 39727. It was isolated as a complex of antibiotics with similar structures and antimicrobial activities (4). Among glycopeptides, these are the first to have significant activity against Neisseria gonorrhoeae. The molecular structures of the two principal components (factors B and A) and of two minor components were recently elucidated (4, 9). All of them contain mannose and a glycolipid group. The only difference between factors A and B is the length of their fatty acid chains (n-undecanoic acid in A, isododecanoic acid in B). The presence of a glycolipid (also found in teicoplanin and aridicins) appears to be correlated with a longer elimination half-life in animals and humans (5, 7). Subcutaneously (s.c.) administered A40926 is effective in curing experimental septicemia, and preliminary data indicated that A40926 has a particularly long half-life in mice (4).The present study of male rats given single 10-mg/kg (body weight) doses was conducted to define the rate and the extent of distribution and elimination of A40926 after intravenous (i.v.) Plasma kinetics. Blood samples were collected under light ether anesthesia by puncture of the retro-orbital sinus with heparinized pipettes at the following times after administration: 0.05 (i.v.) or 0.5 (s.c.), 1, 2, 4, 8, 12, 24, 36, 48, 72, and 96 h. Samples were centrifuged at 1,500 x g at room temperature, and the plasma was separated. Food was offered to the animals 4 h after administration of antibiotic.Urinary recovery. Urine samples were collected at 12, 24, 48, 72, 96, and 120