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Antimicrobial Agents and Chemotherapy, March 2004, p. 739-746, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.739-746.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin , and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

Peter J. Petersen,^1* T. Z. Wang,² Russell G. Dushin,² and Patricia A. Bradford¹

Infectious Disease Research, Microbiology,¹ Chemical and Screening Sciences, Medicinal Chemistry, Wyeth Research, Pearl River, New York 10965²

Received 4 August 2003/ Returned for modification 9 November 2003/ Accepted 22 November 2003

Top Abstract Introduction Materials and Methods Results Discussion References

 
AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC₉₀s], 0.03 to 0.06 µg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC₉₀s, 0.12 and 0.25 µg/ml, respectively) as well as against streptococcal strains (MIC₉₀s, 0.008 to 0.03 µg/ml). AC98-6446 demonstrated bactericidal activity in terms of the reduction in the viable counts (>3 log₁₀ CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log₁₀ CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.

Top Abstract Introduction Materials and Methods Results Discussion References

 
There has been a dramatic increase in the incidence of infections due to gram-positive bacteria during the past 20 years (16, 21, 28, 36). According to one SENTRY study, gram-positive cocci (Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and streptococci) account for 54% of all bloodstream infections (27). The emergence and spread of Streptococcus pneumoniae strains resistant to penicillins, glycopeptide-resistant enterococci, and methicillin-resistant staphylococci are now recognized as global problems (1). Especially problematic are multiple-antibiotic-resistant strains of S. pneumoniae, S. aureus, and enterococci (19). The isolation of S. aureus strains with intermediate resistance to glycopeptide antibiotics (glycopeptide-intermediate S. aureus [GISA]) has been reported from Japan and other parts of Asia, the United States, and Europe (34). In addition, the recent report of vancomycin-resistant S. aureus (2) has introduced a further complication into an already dire situation. This alarming increase in the incidence of infections caused by resistant gram-positive bacteria has sparked renewed interest in the pursuit of novel antibiotics. However, most of the "novel" agents introduced into research and clinical practice are new derivatives of compounds that have existed for many years.

The mannopeptimycins are a truly novel class of natural-product glycopeptide antibiotics produced by Streptomyces hygroscopicus. They were isolated as a partially purified complex and were referred to as "AC98" in the original American Cyanamid patent issued in 1970. The molecular structure and individual components were not delineated due to technical limitations of the era. The complex, however, was shown to possess in vitro and in vivo activities against gram-positive bacteria. Due to this limited spectrum of activity only against gram-positive bacteria, the complex was not considered for further development into a therapeutic agent. However, because of the increasing problem of resistance among gram-positive organisms, a retrospective reevaluation of previous natural-product leads was undertaken. The AC98 complex was separated into its individual components and fully characterized (14). The individual components of the complex are referred to as mannopeptimycin through . Three of these components (, , and ), which are simple isovalerate esters of the component, displayed moderate to good in vitro activity against susceptible gram-positive bacterial strains as well as methicillin-resistant S. aureus (MRSA), methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant enterococci, and penicillin-resistant S. pneumoniae (14, 30).

Biosynthetic and semisynthetic approaches to the production of a modified mannopeptimycin derivative with improved in vitro activity was initiated at Wyeth Research. AC98-6446 (Fig. 1) is a semisynthetic glycopeptide antibiotic related to the natural product mannopeptimycin (AC98-1). AC98-6446 is a ketal derivative of a modified mannopeptimycin core structure that is produced in one or two synthetic steps from fermented analogs of mannopeptimycin (R. G. Dushin, T. Z. Wang, G. Fortier, S. Iera, M. Papamichelakis, L. Richard, J. Sellstedt, and S. Shah, Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. F352, 2002). This core structure is also a variant of the natural product produced by certain mutant strains of S. hygroscopicus. In this study the comparative in vitro activities (the MICs and time-kill kinetics) of AC98-6446 and other antimicrobial agents were evaluated against a variety of recent clinical gram-positive pathogens, including multiply drug-resistant strains.

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FIG. 1. Chemical structure of AC98-6446.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Organisms Routine clinical isolates were collected from various medical centers in the United States and Canada between 1990 and 2001. Identification of the isolates in each culture was performed by conventional methodologies. Staphylococci were identified with the Staph Trac system (bioMerieux, Hazelwood, Mo.); the identities of isolates classified as S. aureus were also confirmed by a coagulase test. Methicillin resistance in S. aureus was determined by growth on a Trypticase soy agar plate containing 6 µg of oxacillin per ml plus 2% NaCl (31) and was confirmed by determination of the oxacillin MICs in the presence of 2% NaCl. The GISA strains were obtained from the Network on Antibiotic Resistance in Staphylococcus aureus (http://narsaweb.narsa.net) as described previously (25). S. pneumoniae strains were identified with the API 20 Strep system (bioMerieux). Penicillin-resistant (MICs, 2 µg/ml) S. pneumoniae isolates were obtained from A. Barry, Clinical Microbiology Institute, Tualatin, Oreg., and S. Block, Bardstown, Ky. Enterococci were identified by biochemical tests, as recommended by Facklam and Collins (8). Strains of vancomycin-resistant enterococci were obtained from previously described sources (35). All isolates were stored frozen in skim milk-50% glycerol at -70°C.

Antibiotics Standard powders of all drugs were used. AC98-6446 and tigecycline (GAR-936) were obtained from Wyeth Laboratories, Pearl River, N.Y.; teicoplanin was obtained from Marion Merrell Dow Inc., Kansas City, Mo.; vancomycin, erythromycin, and amoxicillin were obtained from Sigma Chemical Co., St. Louis, Mo.; and levofloxacin was obtained from The R. W. Johnson Pharmaceutical Research Institute, Princeton, N.J. For all experiments AC98-6446 was dissolved in dimethyl sulfoxide (12.8 mg/ml) and a small quantity (10 µl) was diluted in 1 ml of 30% bovine serum albumin (BSA; Sigma Chemical Co.). This stock solution was then brought to volume with broth (6.99 ml). The final drug and BSA concentrations in the first microtiter well after inoculation were 8 µg/ml and 1.9%, respectively, with each subsequent well having half the concentration of drug and BSA used in the previous well. The use of BSA as an adjuvant presumably prevents the binding of AC98-6446 to the polystyrene microdilution plate. Standard powders of the comparative antibiotic were dissolved in an appropriate solvent and then diluted in broth. Appropriate solvent (dimethyl sulfoxide) and diluent (BSA) controls were included to discount interference with growth.

Antimicrobial susceptibility testing The in vitro activities of the antibiotics were determined by the broth microdilution method, as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) (23), with Mueller-Hinton II broth (BBL Microbiology Systems, Cockeysville, Md.). Microtiter plates containing serial dilutions of each antimicrobial agent were inoculated with each organism to yield the appropriate density (10⁵ CFU/ml) in a 100-µl final volume. The plates were incubated for 18 to 22 h at 35°C in ambient air. The MIC for all isolates was defined as the lowest concentration of antimicrobial agent that completely inhibited the growth of the organism, as detected with an unaided eye.

Time-kill assays Time-kill assays were performed by the broth macrodilution method, in accordance with the NCCLS guidelines (22). A starting inoculum of approximately 10⁶ CFU/ml and a final concentration of the antibiotic equal to four times the MIC were used in these assays. For the concentration-dependent killing curve studies, various multiples of the MICs were used to detect differences in killing. Flasks containing 50 ml of Mueller-Hinton II broth (supplemented with 5% horse blood for S. pneumoniae) with the appropriate antimicrobial agent were inoculated with 50 ml of the test organism in logarithmic growth phase. Test flasks (250 ml) were incubated with shaking (150 rpm) in a 35°C water bath (with periodic shaking used for S. pneumoniae). Aliquots were removed at 0, 2, 4, 6, and 24 h for the determination of viable counts. Serial dilutions were prepared in sterile 0.85% sodium chloride solution. The diluted samples (0.05 ml) were plated onto appropriate agar plates (Trypticase soy agar [TSA] or TSA with 5% sheep blood) with a spiral plater (Don Whitley Scientific Ltd.). The plates were incubated at 35°C in ambient air for 18 to 22 h, and the number of colonies was determined on a ProtoCOL plate reader plater (Don Whitley Scientific Ltd.). Killing curves were constructed by plotting the log₁₀ CFU per milliliter versus time over 24 h, and the change in bacterial concentration was determined. Bactericidal activity was defined as a reduction of 99.9% (3 log₁₀) of the total number of CFU per milliliter in the original inoculum. Bacteriostatic activity was defined as maintenance of the original inoculum concentration or a reduction of less than 99.9% (<3 log₁₀) of the total number of CFU per milliliter in the original inoculum.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The in vitro activities of AC98-6446 against a spectrum of recently recovered clinical isolates are displayed in Tables 1 to 3. The activity of AC98-6446 was compared to those of two other glycopeptide antibiotics, vancomycin and teicoplanin, as well as tigecycline (GAR-936; a glycylcycline), levofloxacin (a quinolone), erythromycin (a macrolide), and amoxicillin (a penicillin). The comparative in vitro activities of AC98-6446 and antibiotics against staphylococcal strains are displayed in Table 1. Overall, AC98-6446, which had MICs at which 90% of isolates are inhibited (MIC₉₀s) of 0.03 to 0.06 µg/ml, demonstrated potent in vitro activity against all of the staphylococcal isolates, including methicillin-resistant and GISA strains. AC98-6446 was 8- to 64-fold more active than tigecycline (MIC₉₀s, 0.5 to 2 µg/ml) against these staphylococcal strains. AC98-6446 also was more active than the other glycopeptide antibiotics, vancomycin and teicoplanin (MIC₉₀s, 1 to >8 µg/ml), against all of the glycopeptide-susceptible staphylococcal strains tested. The activity of AC98-6446 exceeded those of vancomycin and teicoplanin against the GISA strains by 128-fold (MIC₉₀s, 0.06, 8, and 8 µg/ml, respectively). The activity of AC98-6446 surpassed the activities of levofloxacin, erythromycin, and amoxicillin by at least 256-fold against the MRSA, methicillin-resistant coagulase-negative staphylococcal, and GISA strains (MIC₉₀s, >8 µg/ml). AC98-6446 was twofold or more active than levofloxacin, erythromycin, and amoxicillin against susceptible staphylococcal strains (MIC₉₀s, 0.25 to > 8 µg/ml).

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TABLE 1. Comparative in vitro activities of AC98-6446 and other antibiotics against recent staphylococcal clinical isolates

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TABLE 3. Comparative in vitro activities of AC98-6446 and other antibiotics against recent streptococcal clinical isolates

AC98-6446 showed good in vitro activity against the enterococcal strains, including vancomycin-resistant isolates, with MIC₉₀s of 0.12 to 0.25 µg/ml (Table 2). AC98-6446 was eight times more active than vancomycin (MIC₉₀, 2 µg/ml) and had activity equivalent to that of teicoplanin or four times greater than that of teicoplanin (MIC₉₀s, 0.25 and 1 µg/ml, respectively) against vancomycin-susceptible enterococcal isolates. The activity of AC98-6446 exceeded those of the two glycopeptide antibiotics, levofloxacin, erythromycin, and amoxicillin against vancomycin-resistant enterococcal strains by a large margin (MIC₉₀s, 4 to >8 µg/ml). AC98-6446 was at least four times more active than levofloxacin, erythromycin, and amoxicillin against the vancomycin-susceptible strains tested (MIC₉₀s, 1 to >8 µg/ml) and was two to eight times more active than tigecycline against all enterococcal isolates tested (MIC₉₀s, 0.25 to 1 µg/ml).

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TABLE 2. Comparative in vitro activities of AC98-6446 and other antibiotics against recent enterococcal clinical isolates

The activity of AC98-6446 against S. pneumoniae isolates, including penicillin-resistant, penicillin-intermediate, and penicillin-sensitive isolates, is shown in Table 3. AC98-6446 demonstrated excellent activity against the S. pneumoniae strains tested (MIC₉₀s, 0.008 µg/ml). Overall, the activity of AC98-6446 was similar to that of teicoplanin (MIC₉₀s, 0.008 to 0.03 µg/ml) and higher than those of the other antibiotics tested. Against the penicillin-resistant strains the activity of AC98-6446 exceeded those of the comparative antibiotics by 1 to 9 twofold dilutions. AC98-6446 also demonstrated similar potent activity against Streptococcus pyogenes and Streptococcus agalactiae isolates (MIC₉₀s, 0.03 µg/ml) (Table 3). The other antibiotics showed good in vitro activities against the S. pyogenes and S. agalactiae strains (MIC₉₀s, 0.008 to 1 µg/ml).

The results of the time-kill kinetic studies with AC98-6446 against 15 gram-positive isolates are summarized in Table 4 and Fig. 2. By 24 h AC98-6446 at four times the MIC reduced the viable counts of three staphylococcal isolates and two streptococcal isolates below the level that indicated that it was bactericidal. The balance of the staphylococci and streptococci showed reductions in viable counts of 1.6 to 2.7 log₁₀ CFU/ml, with the majority of the reduction in counts being greater than 2.4 log₁₀ CFU/ml. Vancomycin, which caused a reduction in viable counts of 1.7 to 4.1 log₁₀ CFU/ml, demonstrated similar patterns of activity against the staphylococcal and streptococcal isolates. AC98-6446 and vancomycin reduced the viable counts of two vancomycin-susceptible enterococcal strains (reductions of 1.9 to 2.4 log₁₀ CFU/ml); however, the reduction was only to the level that indicated bacteriostatic activity. Levofloxacin demonstrated bactericidal activity against three of the four vancomycin-resistant enterococcal strains (2.8 to 4.2 log₁₀ CFU/ml reduction). AC98-6446 demonstrated marked reductions in the viable counts of the VanB strains, which indicated bacteriostatic activity (reductions of 1.5 and 2.5 log₁₀ CFU/ml); but it was less effective in reducing the loads of the VanA bacterial strains (reductions of 0.2 and 0.6 log₁₀ CFU/ml). AC98-6446 demonstrated concentration-dependent killing of S. aureus ATCC 29213 at twofold increasing concentrations of 1 through 32 µg/ml (Fig. 3). Doubling of the concentration of AC98-6446 (1 through 32 µg/ml) resulted in a stepwise increase in the rate of killing for each doubling dilution. In contrast, as expected, vancomycin demonstrated time-dependent killing of S. aureus ATCC 29213 (Fig. 3). The reductions in the number of log₁₀ CFU per milliliter from 2 through 24 h were identical at doubling concentrations (2 through 64 µg/ml) of vancomycin.

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TABLE 4. Reduction in initial inoculum concentration after 24 h of incubation with AC98-6446, vancomycin, or levofloxacin at four times the MIC

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FIG. 2. Time-kill curves of AC98-6446 and vancomycin against S. aureus GC1131 (MRSA) (A), Enterococcus faecalis GC4552 (B), and S. pneumoniae GC1894 (penicillin resistant) (C).

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FIG. 3. Effects of the concentrations of AC98-6446 (concentration dependent) (A) and vancomycin (time dependent) (B) on the killing of S. aureus ATCC 29213.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Gram-positive cocci are responsible for the alarming increase in nosocomial and community-acquired infections (15, 16, 21, 27, 28, 36). Clearly, antimicrobial resistance among gram-positive cocci is now recognized as an international problem with global implications (1). The rise in the number of multidrug-resistant gram-positive isolates has exposed the severely limited therapeutic options that are available (19). The need for new antibacterial compounds with activity against multiresistant gram-positive pathogens is clearly evident.

The response to the challenge of overcoming bacterial resistance in gram-positive bacteria has produced a number of promising new compounds. Tigecycline (GAR-936) (32), a glycylcycline undergoing phase III clinical trials, has been shown to have excellent activity against gram-positive and gram-negative organisms, including tetracycline-resistant organisms, without any cross-resistance (9, 25, 26). Also in development are daptomycin (33), ketolides (4, 5, 20), quinolones, and a vancomycin derivative with enhanced activity against gram-positive organisms (5, 10, 13, 37). Recently, quinupristin-dalfopristin (24) and an oxazolidinone (3, 7) have been approved for clinical use. These agents, however, have caused multiple adverse effects and have become associated with patterns of significant resistance (11, 12, 15, 18). The continued development of new antibacterial agents is important to overcome the present difficulties with the treatment of infections caused by resistant gram-positive organisms.

Mannopeptimycins through are recently described novel cyclic glycopeptide natural-product antibacterial agents (14, 30). The unique mode of action of this family of compounds has recently been shown to be the inhibition of cell wall biosynthesis by binding to lipid II, and this binding is not related to that of other lipid II binding antibiotics (29, 30). The structure-activity relationship of mannopeptimycins , , , and is related to the location of a single isovaleryl group on the terminal mannose sugar of the disaccharide domain (30). The activities of these compounds against gram-positive organisms vary from poor to moderately good, depending on the position of the isovaleryl group. This finding led to a chemical program targeting modifications of the AC98 structure on this mannose residue, as well as other positions of the molecule, to increase the potency of this family of compounds. Following the synthesis of over 300 semisynthetic compounds, AC98-6446 emerged as the lead compound in this series (Dushin et al., 42nd ICAAC). AC98-6446 is a ketal derivative of a modified AC98 core structure. The change in the core consists of the replacement of a ß-methyl-phenylalanine with a cyclohexyl alanine residue (Fig. 1).

The novel antibiotic AC98-6446, a unique cyclic glycopeptide antibiotic, possesses potent in vitro activity against susceptible and resistant gram-positive pathogens, including multiply resistant strains. Overall, AC98-6446 was the most active antibiotic tested in this comparative study. AC98-6446 demonstrated similar activities against methicillin-susceptible and -resistant staphylococci. In addition, AC98-6446 maintained this activity against GISA isolates. AC98-6446 demonstrated equivalent activity against both vancomycin-resistant and -susceptible enterococci. There was no cross-resistance to enterococcal strains possessing either the VanA or the VanB resistance determinant. AC98-6446 showed excellent activity against all streptococcal strains tested. In addition, AC98-6446 demonstrated similar activities against penicillin-resistant, penicillin-intermediate, and penicillin-susceptible S. pneumoniae isolates. There was no cross-resistance by strains resistant to vancomycin, teicoplanin, erythromycin, levofloxacin, or amoxicillin.

The ability of a compound to demonstrate bactericidal activity is an attractive attribute for any antimicrobial agent. However, the ability of in vitro bactericidal tests to predict therapeutic efficacy has many technical and biological problems (6, 17). Nevertheless, many marketed antibiotics (i.e., tetracyclines and macrolides) which fail to demonstrate bactericidal activity in vitro have successfully been used to treat serious infections for decades. Time-kill kinetic studies were performed to assess the in vitro activity of AC98-6446 against a variety of gram-positive organisms, including resistant strains. In general, these results indicate that AC98-6446 is bactericidal for most staphylococcal and streptococcal isolates and bacteriostatic for most enterococcal isolates. It is noteworthy that AC98-6446 demonstrated a rate of killing similar to that of vancomycin and resulted in the same outcome as that achieved with vancomycin but with a significantly lower concentration of compound. This observation, combined with the concentration-dependent killing demonstrated by AC98-6446, suggests that increased concentrations of antibiotic should result in increased rates of killing. The dramatic potency of AC98-6446 against problematic gram-positive pathogens, its unique mechanism of action, and its bactericidal activity make it an attractive candidate for further development.

 
We thank Heather Hartman for technical assistance.

 
* Corresponding author. Mailing address: Infectious Disease Research, Wyeth Research, Bldg. 200/Rm. 3301, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (845) 602-3070. Fax: (845) 602-5671. E-mail: petersp{at}wyeth.com.

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Antimicrobial Agents and Chemotherapy, March 2004, p. 739-746, Vol. 48, No. 3
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.3.739-746.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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