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Antimicrobial Agents and Chemotherapy, August 1998, p. 1985-1989, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Efficacy of MK-991 (L-743,872), a
Semisynthetic Pneumocandin, in Murine Models of
Pneumocystis carinii
Mary Ann
Powles,1,*
Paul
Liberator,1
Jennifer
Anderson,1
Yashwant
Karkhanis,1
James F.
Dropinski,1
F. Aileen
Bouffard,1
James M.
Balkovec,1
Hisashi
Fujioka,2
Masamichi
Aikawa,2
Diane
McFadden,3 and
Dennis
Schmatz1
Merck Research Laboratories, Rahway,
New Jersey 070651;
Institute of
Pathology, Case Western Reserve University, Cleveland, Ohio
441062; and
Department of
Microbiology and Immunology, Stanford School of Medicine, Stanford,
California 94305-54023
Received 10 December 1997/Returned for modification 12 March
1998/Accepted 6 May 1998
 |
ABSTRACT |
In addition to its potent efficacy in animal models
against Candida sp., Aspergillus fumigatus,
and Histoplasma capsulatum, the clinical
candidate pneumocandin MK-991 (formerly L-743,872) was also extremely
potent against Pneumocystis carinii in models of
immune-compromised animals. MK-991 was approximately 14 times more
potent than the original natural product lead, pneumocandin B0. The 90% effective dose (ED90)
of MK-991 for cyst clearance in the rat model for
pneumocystis was 0.011 mg/kg of body weight when delivered
parenterally for 4 days twice a day (b.i.d.). In a mouse model,
under the same experimental parameters, the ED90 was 0.02 mg/kg. MK-991 was also effective orally, with an ED90 for
cyst clearance of 2.2 mg/kg against acute infection in
rats (b.i.d. for 4 days). Complete prevention of P. carinii
development was achieved in immunocompromised mice at a daily
oral dose of 2.25 mg/kg. As reported previously for other
pneumocandins and echinocandins, MK-991 selectively prevented the
development of P. carinii cysts. When used as a
prophylactic agent, neither stage of the organism appeared in the lungs
of animals. In response to an acute infection, cysts were
eliminated rapidly, while trophozoite forms persisted. Despite
good efficacy as an oral agent in murine models, the low oral
absorption of this class may limit the use of MK-991 to
parenteral therapy.
| |
INTRODUCTION |
Pneumocystis
carinii is one of the most common and serious opportunistic
infections in patients with AIDS, as well as in those receiving
immunosuppressive therapy as a result of organ transplantation or cancer chemotherapy. The most widely used agent for the treatment and prevention of P. carinii pneumonia (PCP),
trimethoprim-sulfamethoxazole (TMP-SMZ), has a high incidence of
adverse reactions in AIDS patients (2). Rapid oral
desensitization to TMP-SMZ has been attempted (5, 8, 10),
and while initial results are positive, studies have been
limited to small numbers of patients, and there is clearly a need for a
new class of compounds to treat PCP.
A novel natural product, pneumocandin B0, originally
isolated from a fermentation of Glarea lozoyensis, was found
to have activity in an experimental rat model for PCP (13).
Synthetic chemical modifications of the parent structure have
resulted in more potent and soluble compounds
(12). The pneumocandins act by inhibiting the synthesis of
- 1,3-glucan, a major component of the cyst wall of
P. carinii (7). The lack of a mammalian -1,3-glucan synthase counterpart should provide a superior
therapeutic window over standard PCP treatments, such as TMP-SMZ and
pentamidine.
While -1,3-glucan represents a major portion of the wall of the
cyst, it is not found in great abundance in the trophozoite form of the organism. From previous studies (13), we
know that short-term treatment (4 days) with pneumocandin analogs
does not have a significant effect on trophozoites. Treatment
over a period of 2 weeks (the standard length of treatment for known
PCP agents) results in no significant increase or decrease in
the level of trophozoites. This result suggests that inhibition of cyst
proliferation has an effect on the ability of the trophozoites
to multiply. Finally, when prophylactic effects of the
pneumocandins were evaluated, inhibition of the cyst form of the
organism was found to result in inhibition of the trophozoite
form as well, implying that the cyst stage is required for trophozoite
proliferation (11).
The efficacy of one of the most potent semisynthetic pneumocandins,
MK-991, against PCP is evaluated here. This compound was evaluated
orally (p.o.) and parenterally in murine models for PCP. Short-term (4 day) and long-term (as much as 21 days) uses, as well as prophylactic
use, were evaluated. In addition, the effects of the drug on the
organization of the cyst and localization of the drug in the cyst wall
after 2 days of drug treatment were evaluated.
| |
MATERIALS AND METHODS |
Compound.
The MK-991 compound used in these studies
was synthesized by the Merck Synthetic Chemical Research Group from
natural products produced and isolated by the Merck Natural Product
Drug Discovery Group. MK-991 is water soluble (>20 mg/ml), and all
experiments were performed with the compound in sterile water.
Animals.
The dexamethasone-immunosuppressed animal
model used in these studies has been described elsewhere (4,
12). For these studies, C3Heb/FeJ mice were obtained from Jackson
Laboratories (Bar Harbor, Maine) and Sprague-Dawley rats were
obtained from Taconic Labs (Germantown, N.Y.). All animals were VAF
inbred strains raised under barrier condi- ions and housed in
microisolator cages. The mice received 4 mg of dexamethasone
(Butler, Columbus, Ohio) per liter in their drinking water to cause
immunosuppression, while the rats received 1.5 to 2.0 mg/liter. For
treatment of acute disease, the animals were
immunosuppressed 6 to 7 weeks prior to the start of
treatment, whereas for the prophylactic study, treatment
with MK-991 began on the day on which immunosuppressive therapy was initiated. All animals also received
1 g of tetracycline per liter in their drinking water for
prevention of bacterial infections. Food (23% protein
rodent chow; Purina, St. Louis, Mo.) and water were supplied ad
libitum.
Efficacy studies.
For acute therapy studies, animals were
treated with MK-991 subcutaneously (s.c.) twice a day (b.i.d.) for as
much as 21 days or were gavaged for p.o. treatment. Prophylactic
treatment was administered once a day (q.d.) for 6 weeks by gavage, and
treatment was initiated at the start of immunosuppression. In studies
in which TMP-SMZ was used for comparison, the drug was delivered in the
drinking water at a dose of 200 mg of TMP-1,000 mg of SMZ per liter of
water. The dose levels for individual experiments are indicated in the
figure legends. The 90% effective dose (ED90) was defined
as the effective dose for 90% cyst clearance relative to vehicle
controls. All data are the mean numbers (log10) of cysts ± standard errors (indicated by error bars).
Evaluation of lung tissue.
Excised lungs were
homogenized in 5.0 ml of phosphate-buffered saline (Sigma) with a
Brinkmann homogenizer (Brinkmann Instruments, Westbury, N.Y.) set at
speed no. 3 for approximately 5 s. Homogenates were centrifuged
(Beckman GPR centrifuge) at 1,700 × g for 10 min. The
erythrocytes were lysed by resuspension of the pellet in 5.0 ml of
a 0.85% ammonium chloride (Mallinckrodt, Paris, Ky.) solution and
incubated for 5 min in a 37°C water bath and were then
centrifuged at 1,700 × g (10 min). The pellets were
washed once in saline, and the final pellets were resuspended in 100 µl of saline for mice and 2 ml of saline for rats. A 5.0-µl aliquot of each sample was evenly applied and air dried onto Teflon-coated microscope slides with a fixed surface area (11-mm circles; Carlson Scientific, Peotone, Ill.). The extent of disease for each animal was
determined by microscopic analysis of stained slides. The total numbers
of cysts per animal lung were determined by quantitating the
numbers of cysts in 20 microscope fields (×1,000) of homogenized lung
tissue on slides fixed with ether-sulfuric acid and were stained with
Toluidine Blue O (14). The total number of cysts per animal
lung was determined as a function of the surface area on the slide, the
volume of the applied sample, and the total volume of the processed
homogenate. The limit of detection for cyst counts was a log mean of
3.36.
Quantitation of P. carinii trophozoites (nuclei) was
achieved by hybridization with two P. carinii-specific
genomic DNA probes essentially as described previously
(6). Total genomic DNA was prepared from lung tissue of
individual mice, quantitated, and immobilized on a nylon
membrane. The hybridization probes (clones B13-2 and A2-1) were
single-copy genomic clones isolated from a rat P. carinii isolate. Both of these clones cross-hybridize to genomic
DNA prepared from a murine P. carinii isolate but do not hybridize to genomic DNA prepared from murine tissues, including heart, intestine, and kidney tissues. The probes also do
not hybridize to genomic DNAs prepared from the following organisms:
Trypanosoma brucei, Eimeria tenella,
Toxoplasma gondii, Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans,
Aspergillus nidulans, Pseudomonas aeruginosa,
Streptococcus pneumoniae, Aspergillus fumigatus,
and cytomegalovirus-infected human foreskin fibroblasts. Hybridization
signals were quantitated with a PhosphorImager (Molecular Dynamics,
Inc.).
Lung tissue prepared for electron microscopy was fixed according to the
procedure described by Nollstadt et al. (
9).
| |
RESULTS |
Parenteral treatment with MK-991 in rats and mice.
Parenteral titrations of MK-991 in rats (Fig.
1A) and mice (Fig. 1B) after 4 days of
treatment resulted in ED90s for cyst clearance of 0.011 and
0.02 mg/kg of body weight, respectively. This represents at least a
14-fold improvement in the ED90 for rats compared with that
for the parent compound pneumocandin B0, which is 0.15 mg/kg (12).
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FIG. 1.
(A) Rats with acute P. carinii
infections were treated s.c. b.i.d. for 4 days with 0.075, 0.038, 0.019, or 0.009 mg of MK-991 per kg. There were five rats in
each group. The ED90 was estimated to be 0.011 mg/kg. (The
limit of detection was 4.66.) (B) Mice with acute P. carinii infections were treated s.c. b.i.d. for 4 days
with various doses of MK-991. There were five mice in each group. The
ED90 was determined to be 0.02 mg/kg. (The limit of
detection was 3.36.)
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|
P. carinii cyst clearance in rats and mice.
A 90% reduction in the number of cysts relative to controls was seen
in rats after 4 days of s.c. treatment with 1.0 mg of MK-991 per
kg b.i.d. (Fig. 2A) and in mice after 4 days of treatment with 0.03 mg/kg b.i.d. (Fig. 2B). In comparison,
mice treated with TMP-SMZ did not reach a 90% reduction in the
level of cysts until almost 2 weeks of treatment (Fig. 2B). This
is similar to a result obtained previously with TMP-SMZ
(11).
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FIG. 2.
(A) Rats with acute P. carinii
infections were treated for 21 days with 1 mg of MK-991 per kg b.i.d.
or were treated with TMP-SMZ (Bactrim) via their drinking water (200 mg
of TMP-1,000 mg of SMZ/liter of water). A 90% reduction in the number
of cysts was seen with MK-991 after 4 days of treatment. In
contrast, the Bactrim-treated group did not show a 90% reduction until
after >1 week of treatment. (The limit of detection, scored as
one cyst per 20 fields, was 4.66.) (B) Mice with acute P. carinii infections were treated with 0.31-mg/kg MK-991 b.i.d. or
Bactrim in water for 14 days. There were 15 mice per group. While a
90% reduction in cysts was seen at 4 days with MK-991, the
Bactrim-treated group did not reach 90% reduction until almost 2 weeks
of treatment. (The limit of detection for this experiment was 3.36.)
|
|
P. carinii trophozoite clearance in rats.
When
lung tissue from the previous experiment was evaluated for nuclei
after 21 days of treatment, rats in the MK-991-treated group showed a
66.3% reduction in the level of nuclei compared to controls, while
rats in the TMP-SMZ-treated group showed a 99.9% reduction in nuclei
(Fig. 3).
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FIG. 3.
Trophozoite clearance in rats. Rats with acute P. carinii infections treated for 21 days with 1 mg of MK-991 per kg
b.i.d. or Bactrim in water were evaluated for trophozoites with a
P. carinii-specific DNA probe. Rats in the MK-991-treated
group showed a 66.3% reduction in the level of trophozoites, while
rats in the Bactrim-treated group showed a 99.9% reduction in the
number of trophozoites.
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|
Oral treatment with MK-991 in rats.
MK-991 was gavaged
b.i.d. in a dose titration of 0.78 to 6.25 mg/kg for 4 days. The
ED90 for cyst clearance in rats was 2.2 mg/kg (Fig.
4).
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FIG. 4.
Oral efficacy in rats. Rats with acute P. carinii infections were gavaged b.i.d. for 4 days with 0.78, 0.163, 3.13, or 6.25 mg of MK-991 per kg. Each group contained five
rats. The ED90 was estimated to be 2.2 mg/kg. (The limit of
detection was 4.66.)
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|
Oral prophylaxis of MK-991 in mice.
In a prophylaxis study,
mice were treated q.i.d. for 8 weeks with MK-991. Immunosuppression
with dexamethasone coincided with the start of drug treatment. The
ED90 for cyst reduction was 2.25 mg/kg (Fig.
5). When nuclei were quantitated with a
P. carinii-specific DNA probe, a 90% difference in the
number of nuclei compared to controls, was seen with 1.1 mg of MK-991
per kg (Fig. 6).
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FIG. 5.
Oral prophylaxis of MK-991 in mice. Mice with latent
P. carinii infections were treated with MK-991 once a
day for 8 weeks at doses of 6.25, 3.13, 1.56, or 0.78 mg/kg. Treatment
began at the start of immunosuppression. The ED90 for cyst
reduction was estimated to be 2.25 mg/kg. (The limit of detection was
3.36.)
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FIG. 6.
Efficacy of daily oral prophylactic use of MK-991 as
measured by hybridization with a P. carinii-specific DNA
probe. Total genomic DNA prepared from lungs of individual animals was
immobilized on a nylon membrane in three dilutions, 25 i.e.,
(column i), 2.5 (column ii), and 0.25 (column iii) µg. (A) P. carinii-specific hybridization in nonmedicated, infected control
mice (n = 15); (B, C, D, and E) results from mice
treated with 0.78 (n = 11), 1.56 (n = 20), 3.13 (n = 20), and 6.25 (n = 20)
mg of MK-991/kg, respectively. The ED90 for prevention of
P. carinii trophozoites was estimated to be 1.1 mg/kg.
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|
Localization of drug in the cyst wall of P. carinii.
Lung tissue from infected rats was fixed and
prepared for electron microscopy. The wall of a normal cyst contains an
electron-dense layer and an electron-lucent layer. The proposed
location of -1,3-glucan is the electron-translucent layer (Fig.
7A). When a portion of the same sample
was fixed for immunogold electron microscopy and incubated with
antisera specific for -1,3-glucan, the -1,3-glucan antibody
reacted only with the translucent layer of the cell wall (Fig. 7C). No
reactivity was seen with the surrounding lung tissue or the
trophozoites. In cysts from rats treated for 2 days with another
pneumocandin, L-733,560 (12), the electron-lucent layer was
absent, the electron-dense layer was thickened, and the wall of the
cyst lost the typical rigid shape (Fig. 7B). In treated lung tissue
fixed with immunogold and incubated with antibody to pneumocandin (Fig.
7D), the antibody was specific to the area corresponding to the
remnants of the translucent layer, strongly suggesting that the
pneumocandins localize in the cyst wall.
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FIG. 7.
(A) Mature P. carinii cyst containing
trophozoites in rat lung tissue. The electron-lucent layer of the cyst
wall is the proposed location of -1,3-glucan. (B) Cyst from a rat
with acute PCP treated for 2 days with the pneumocandin L-733,560. The
electron-lucent layer is absent, while the electron-dense layer has
thickened and the wall has lost its rigid shape. (C) Section of the
lung sample in panel A fixed for immunogold electron microscopy. The
section was incubated with antiserum specific for -1,3-glucan and
labelled with immunogold. The -1,3-glucan antibody reacts only with
the translucent layer of the cyst wall. There is no reactivity seen
with the surrounding lung tissue or with the trophozoites. (D)
Section of the lung sample shown in panel B. The section was incubated
with antibody made against L-733,560 and then labelled with immunogold.
The antibody specifically targets what is left of the translucent
layer, demonstrating that the pneumocandins localize in the cyst wall
upon treatment of the animal.
|
|
| |
DISCUSSION |
Synthetic chemical modification of the natural
product pneumocandin B0, including reduction
of glutamine and substitution of the hemiaminal with ethylene diamine,
results in the structure of MK-991. These modifications have led to
significant improvement in the activity against P. carinii in murine models. The parenteral activity
of MK-991 in the rat model for PCP is approximately 14-fold greater
than that of the natural product, with an ED90 of 0.011 versus 0.15 mg/kg for pneumocandin B0. For oral treatment
of acute disease, a dose of 2.2 mg/kg is effective at eliminating
90% of the cysts b.i.d. in 4 days. Since the -1,3-glucan
component of P. carinii is specific for the cyst stage
of the organism, treatment of acute disease has little effect on the
trophozoite stage. However, in studies in which MK-991 was given
prophylactically, development of both stages was prevented at a daily
oral dose of 2.25 mg/kg.
These results, combined with the efficacy of MK-991 against other
pathogenic fungi, including C. albicans and A. fumigatus (1, 3), demonstrate the potential
for the use of this compound as a broad-spectrum agent in the
immunocompromised patient. The lack of a mammalian -1,3-glucan
counterpart implies that this class of compounds would provide a safer
alternative to amphotericin B, the most effective drug currently used
for the treatment of systemic fungal infections, which is highly toxic
and not efficacious against PCP. Currently, MK-991 is in development as
a broad-spectrum antifungal agent for parenteral treatment of systemic
infections. Due to the specificity of MK-991 for the cyst stage of
P. carinii, the benefits of treatment with MK-991 for acute
PCP are not known. The more likely scenario would be the use of MK-991
for prophylaxis of PCP. Since parenteral dosing would have limited
applications for prophylaxis and aerosol delivery for prevention of PCP
has proven effective, delivery of MK-991 via aerosol might prove
useful. In a previous study with aerosolized L-693,989
(11), a related pneumocandin, prevention of P. carinii cysts and trophozoites was achieved at a daily dose of 7 µg/lung or a weekly dose of 77.9 µg/lung. Since the parenteral
ED90 for cyst clearance with L-693,989 is 0.15 mg/kg
(4) versus 0.11 (rats) to 0.2 (mice) mg/kg for MK-991, the
delivery dose necessary for aerosol prophylaxis with MK-991 should be
less than the doses described for L-693,989.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Merck Research
Laboratories, Rahway, NJ 07065. Phone: (732) 594-4949. Fax: (732)
594-6708. E-mail: maryann_powles{at}merck.com.
| |
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Antimicrobial Agents and Chemotherapy, August 1998, p. 1985-1989, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
