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Antimicrobial Agents and Chemotherapy, April 1999, p. 738-744, Vol. 43, No. 4
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Antibacterial Activities of a Novel
Glycylcycline, the 9-t-Butylglycylamido Derivative
of Minocycline (GAR-936)
P. J.
Petersen,*
N. V.
Jacobus,
W. J.
Weiss,
P. E.
Sum, and
R. T.
Testa
Infectious Disease Research Section,
Wyeth-Ayerst Research, Pearl River, New York 10965
Received 3 August 1998/Returned for modification 17 November
1998/Accepted 2 January 1999
 |
ABSTRACT |
The 9-t-butylglycylamido derivative of
minocycline (TBG-MINO) is a recently synthesized member of a
novel group of antibiotics, the glycylcyclines. This new derivative,
like the first glycylcyclines, the
N,N-dimethylglycylamido derivative
of minocycline and 6-demethyl-6-deoxytetracycline, possesses activity
against bacterial isolates containing the two major determinants
responsible for tetracycline resistance: ribosomal protection and
active efflux. The in vitro activities of TBG-MINO and the
comparative agents were evaluated against strains with characterized tetracycline resistance as well as a spectrum of recent
clinical aerobic and anaerobic gram-positive and gram-negative bacteria. TBG-MINO, with an MIC range of 0.25 to 0.5 µg/ml, showed good activity against strains expressing tet(M) (ribosomal
protection), tet(A), tet(B),
tet(C), tet(D), and tet(K) (efflux
resistance determinants). TBG-MINO exhibited similar activity against
methicillin-resistant Staphylococcus aureus (MRSA),
penicillin-resistant streptococci, and vancomycin-resistant enterococci
(MICs at which 90% of strains are inhibited, 
0.5 µg/ml). TBG-MINO
exhibited activity against a wide diversity of gram-negative aerobic
and anaerobic bacteria, most of which were less susceptible to
tetracycline and minocycline. The in vivo protective effects of
TBG-MINO were examined against acute lethal infections in mice caused
by Escherichia coli, S. aureus, and
Streptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused by
S. aureus including MRSA strains and strains containing
tet(K) or tet(M) resistance determinants
(median effective doses [ED50s], 0.79 to 2.3 mg/kg of
body weight). TBG-MINO demonstrated efficacy against infections
caused by tetracycline-sensitive E. coli strains as well as
E. coli strains containing either tet(M) or the
efflux determinant tet(A), tet(B), or
tet(C) (ED50s, 1.5 to 3.5 mg/kg). Overall,
TBG-MINO shows antibacterial activity against a wide spectrum of gram-positive and gram-negative aerobic and anaerobic bacteria including strains resistant to other chemotherapeutic agents.
The in vivo protective effects, especially against infections caused by
resistant bacteria, corresponded with the in vitro activity of
TBG-MINO.
| |
INTRODUCTION |
Tetracycline antibiotics were first
isolated at Lederle Laboratories in 1945 and represented a significant
advancement in the treatment of many infections (4, 7).
However, due to an increased incidence of resistance among many
bacteria (27), the use of the tetracyclines has been
relegated to second- and third-line drug categories for most clinical
indications (16, 25). The synthesis of new derivatives
containing the
N,N-dimethylglycylamido (DMG)
substitution at the 9 position of minocycline and of
6-demethyl-6-deoxytetracycline (DMDOT) represented a significant
advance in the tetracycline class of antibiotics (29). These
new derivatives were named the glycylcyclines and were shown to be
active against a wide spectrum of gram-positive and gram-negative
bacteria, including resistant strains (5, 9, 12, 22, 31, 33,
34).
Derivatives in the minocycline series were found to be better tolerated
than the DMDOT series in studies with rats (data not shown). In the
present study we investigated the in vitro activity and in vivo
efficacy of a new member of the glycylcyclines, TBG-MINO, the
9-t-butylglycylamido derivative of minocycline (Fig.
1), which was selected on the basis of
its better tolerability and improved activity against
tetracycline-resistant strains compared with those of
DMG-DMDOT. The activity of TBG-MINO was determined against strains harboring characterized tetracycline resistance determinants and recent clinical isolates. The activities were compared with those
of DMG-DMDOT, DMG-MINO, minocycline, tetracycline, and other antimicrobial agents. The efficacy of TBG-MINO was compared
with those of DMG-DMDOT and minocycline against murine systemic
infections caused by bacterial strains harboring characterized
tetracycline resistance determinants, laboratory strains, and recent
clinical isolates adapted for murine infection.
| |
MATERIALS AND METHODS |
Organisms.
Routine clinical isolates were collected from
various medical centers in the United States and Canada between 1989 and 1994. Identification of each culture was done by conventional
methods, as follows: gram-negative rods with the API 20E system
(Analytab Products, Plainville, N.Y.) and the NF system (Remel, Lenexa, Kans.), anaerobes by the procedure outlined in the Wadsworth
Anaerobic Bacteriology Manual (30), enterococci by
biochemical tests as recommended by Facklam and Collins (6),
streptococci with the API 20 Strep system (Analytab Products), and
staphylococci with the Staph Trac system (Analytab Products).
Staphylococcus aureus was also confirmed by a
coagulase-test. Methicillin-resistance in S. aureus was
determined with a plate containing oxacillin at 6 µg/ml, as described
in the Manual of Clinical Microbiology (28).
Penicillin-resistant (MICs, 
2 µg/ml)
Streptococcus pneumoniae isolates were obtained from A. Barry, Clinical Microbiology Institute, Tualatin, Oreg., and
S. Block, Bardstown, Ky. Strains with tetracycline resistance
determinants and the vancomycin-resistant enterococci were obtained
from the sources described previously (31). All isolates
were stored frozen in skim milk at 
70°C.
Antibiotics.
Standard powders of TBG-MINO, DMG-MINO,
DMG-DMDOT, vancomycin, minocycline, and tetracycline were
obtained from Wyeth-Ayerst Laboratories, Pearl River, N.Y.;
erythromycin was obtained from Sigma Chemical Co., St. Louis, Mo.;
ciprofloxacin was obtained from Bayer Laboratories, West Haven, Conn.;
ceftazidime was obtained from Glaxo Group Research, Ware, Herts, United
Kingdom; and imipenem was obtained from Merck & Co., West Point, Pa.
In vitro susceptibility testing.
The activities of the
antibiotics were determined by the agar dilution method by following
the recommendations of the National Committee for Clinical Laboratory
Standards (20, 21). Mueller-Hinton II agar was used to test
nonfastidious aerobic bacteria. The medium was supplemented with 5%
sheep blood for the testing of streptococcal isolates and 15 µg of
-NAD per ml, 15 µg of hematin per ml, and 5 mg of yeast extract
per ml for the testing of Haemophilis influenzae and
Moraxella catarrhalis. GC agar supplemented with 1%
hemoglobin and 1% IsoVitaleX was used to test Neisseria
gonorrhoeae. Anaerobic bacteria were tested on Wilkins Chalgren
agar supplemented with 5% lysed sheep blood and 0.001% vitamin K. The
inocula, which were adjusted to the recommended densities
(107 CFU/ml for aerobes and 108 CFU/ml for
anaerobes), were applied to the surfaces of the agar plates with a
Steers replicator. Test plates were incubated at 35°C for 18 to
24 h in ambient air for nonfastidious aerobic bacteria and
streptococci and in CO2 for N. gonorrhoeae,
H. influenzae, and M. catarrhalis. Anaerobic
bacteria were incubated in an anaerobic chamber (Coy Laboratories, Ann
Arbor, Mich.) at 35°C for 48 h. The MIC was defined as the
lowest concentration of the antimicrobial agent that completely
inhibited the growth of the organism as detected by the unaided eye.
In vivo efficacy against murine infections.
The
therapeutic effects of the antibiotics were determined against
acute lethal infections in mice (3) caused by
minocycline-susceptible and minocycline-resistant gram-positive and
gram-negative bacteria. Female CD-1 mice from Charles River
Laboratories (weight, 20 ± 2 g each) were challenged by
intraperitoneal injection of 0.5 ml of a bacterial suspension in either
5% hog gastric mucin or broth (10 to 100 50% lethal doses). Five to
six doses of the antibiotic in phosphate-buffered saline (0.01 M; pH
7.4) were administered intravenously (0.2 ml) or orally (0.5 ml) at
0.5 h postinfection. For mice infected with Escherichia
coli JC3272 Tcr tet(B), a second dose of
the antibiotic was given 3 h later. In each test, five animals
were treated with each dose. All the untreated controls died within
48 h of infection. The median effective dose (ED50)
was determined by probit analysis of the 7-day survival ratios pooled
from three separate tests (8).
| |
RESULTS |
In vitro activity against tetracycline-resistant strains.
The
in vitro activity of TBG-MINO against prototype strains possessing
characterized tetracycline resistance mechanisms is summarized in Table
1. TBG-MINO had similar activity (MICs,
0.5 µg/ml) against tetracycline-susceptible and
tetracycline-resistant E. coli strains carrying the efflux
resistance determinants tet(A), tet(B),
tet(C), and tet(D) and the strain carrying the
ribosomal protection resistance determinant tet(M).
TBG-MINO had activity similar to those of DMG-MINO and
DMG-DMDOT against E. coli strains containing
the tet(B) and tet(D) efflux resistance
determinant and the ribosomal protection resistance determinant
tet(M); however, TBG-MINO was more active than
DMG-MINO and DMG-DMDOT against E. coli strains
containing efflux resistance determinants tet(A) and
tet(C). Minocycline demonstrated poorer activity (MIC range, 4 to >32 µg/ml) against all of the E. coli strains
carrying the resistance determinants. TBG-MINO, with MICs of 0.5
µg/ml, was as active as DMG derivatives against the
tet(K) (efflux)- and tet(M)-containing
S. aureus strains. Minocycline was slightly more active
than the glycylcyclines against tet(K)-containing S. aureus but had poorer activity against the three
S. aureus strains containing tet(M).
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TABLE 1.
In vitro activities of TBG-MINO, DMG-MINO,
DMG-DMDOT, minocycline, and tetracycline against strains
with characterized tetracycline resistance determinants
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|
In vitro activity against recent clinical isolates.
TBG-MINO
showed good activity against isolates of methicillin-resistant
S. aureus (MRSA) and methicillin-resistant
coagulase-negative staphylococci (MICs at which 90% of isolates are
inhibited [MIC90s], 1 µg/ml). This activity was
similar to that of minocycline and was 2 to 3 dilutions lower
than those of DMG-MINO and DMG-DMDOT (Table
2).
Against methicillin-susceptible staphylococci, the three
glycylcycline derivatives had equivalent activities (MICs, 0.5
µg/ml). TBG-MINO and the DMG derivatives demonstrated activity against Enterococcus faecalis and Enterococcus
faecium, including vancomycin-resistant strains
(MIC90s, 0.5 µg/ml). The three glycylcyclines, minocycline, and tetracycline exhibited good activity against Streptococcus pyogenes and penicillin-susceptible
S. pneumoniae; however, TBG-MINO and the DMG
derivatives were 32 to 64 times more active than minocycline against
Streptococcus agalactiae and penicillin-resistant
S. pneumoniae. No differences in the activity of
TBG-MINO between penicillin-susceptible and penicillin-resistant S. pneumoniae isolates were noted. In general,
TBG-MINO, with MICs of 1 µg/ml, displayed greater activity than the
other comparative antibiotics, vancomycin, ciprofloxacin, and
erythromycin, against most of the staphylococcal and enterococcal
isolates tested.
TBG-MINO, with a range of MICs of 0.5 to 8 µg/ml, was 4 to 32 times
more active than minocycline against clinical isolates
of
E. coli,
Shigella spp.,
Citrobacter diversus,
Salmonella spp.,
Providencia spp.,
Morganella morganii, and
N. gonorrhoeae (Table
3).
TBG-MINO was generally as active or more active than minocycline
against most strains of
Klebsiella spp.,
Citrobacter freundii,
Enterobacter spp.,
Serratia marcescens,
Proteus mirabilis,
Proteus vulgaris,
Burkholderia cepacia, and
Pseudomonas aeruginosa. In
general, the three glycylcyclines
demonstrated similar activities
against gram-negative isolates;
however, greater activity was
observed with TBG-MINO than with
DMG-MINO or DMG-DMDOT (MIC
90s,
0.5
versus 4 µg/ml, respectively) against
E. coli strains for
which minocycline MICs were elevated (MIC
90, 16 µg/ml).
TBG-MINO,
DMG-MINO, and DMG-DMDOT were generally less active
than ciprofloxacin,
imipenem, and ceftazidime against most
gram-negative bacteria.
However, organisms resistant to
these antibiotics showed no cross-resistance
with the glycylcyclines.
TBG-MINO and the other glycylcycline derivatives, with a range of
MICs of 0.12 to 2 µg/ml, were more active than minocycline
against
Bacteroides spp.,
Prevotella spp.,
Clostridium difficile,
and anaerobic gram-positive
cocci (Table
4). For some members
of the
Bacteroides fragilis group, the MICs of TBG-MINO but not
those of DMG-MINO or DMG-DMDOT were found to be elevated (1 to
2 µg/ml). In general, the three glycylcyclines were more active
than cefoxitin but were less active than imipenem against most
of the
anaerobic bacteria tested.
In vivo efficacy.
Administered as a single intravenous dose,
TBG-MINO showed efficacy against infections caused by
tetracycline-susceptible and tetracycline-resistant
S. aureus and E. coli strains in
mice (Table 5 and
6). Against an infection with
S. aureus Smith, a tetracycline-susceptible strain, all
three compounds, TBG-MINO, DMG-DMDOT, and
minocycline, displayed efficacy (ED50s, 0.64, 0.51, and 0.53 mg/kg of body weight, respectively) when they were
administered intravenously; however, when they were administered
orally, TBG-MINO and DMG-DMDOT were 40- to 60-fold less
efficacious (Table 5). In contrast, when administered orally
minocycline exhibited efficacy equivalent to that achieved when
it was administered intravenously against S. aureus
Smith infection (ED50, 0.52 mg/kg). Due to the poor
efficacy in mice noted when the drugs were given by the oral route, other in vivo tests were performed with only intravenous administration. TBG-MINO and DMG-DMDOT were moderately more
efficacious than minocycline against an infection with S. aureus UBMS 90-2 [a tet(M) (ribosomal
protection)-containing strain] (Table 6). TBG-MINO,
DMG-DMDOT, and minocycline had comparable efficacies against an
infection caused by S. aureus UBMS 88-7, a
tet(K) efflux resistance determinant-containing strain
(ED50s, 2.1, 3.1, and 2.0 mg/kg, respectively).
TBG-MINO and DMG-DMDOT showed protective efficacy against
an infection caused by S. aureus NEMC 89-4 (a tetracycline-susceptible, methicillin-resistant strain), but
minocycline was slightly more effective. Against infections
caused by an MRSA strain containing the tet(M) resistance
determinant (strain ID 4729) and an MRSA strain carrying both
tet(M) and tet(K) resistance determinants (strain
ID 2371), TBG-MINO and DMG-DMDOT showed efficacies which
exceeded that of minocycline by approximately two and five times,
respectively. Comparable efficacies against infections caused by
S. pneumoniae were obtained with TBG-MINO and
DMG-DMDOT, regardless of the strain's susceptibility to
penicillin (range of ED50s, 0.53 to 1.9 mg/kg). Minocycline
was slightly less effective against infections caused by
penicillin-susceptible S. pneumoniae and was >30 times
less effective than the glycylcyclines against a penicillin-resistant
S. pneumoniae infection (ED50, 20 mg/kg).
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TABLE 5.
In vivo activities of TBG-MINO, DMG-DMDOT,
and minocycline against experimental acute lethal
S. aureus Smith infection
in micea
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TABLE 6.
In vivo activities of TBG-MINO, DMG-DMDOT, and
minocycline against experimental acute lethal infections in mice
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|
TBG-MINO, DMG-DMDOT, and minocycline were observed
to have similar efficacies against an infection caused by the
tetracycline-susceptible
strain
E. coli 311, with
ED
50s of 1.7, 1.5, and 3.2 mg/kg, respectively.
Against
infections caused by
E. coli strains containing
tet(A)
or
tet(C) efflux resistance determinants,
TBG-MINO (ED
50s, 1.6
and 1.5 mg/kg, respectively) exhibited
efficacy that was approximately
three times that of DMG-DMDOT
and more than nine times that of
minocycline. Against an
infection caused by
E. coli UBMS 90-4,
a laboratory
strain in which the
tet(M) resistance determinant
mechanism
was inserted, both TBG-MINO and DMG-DMDOT, with
ED
50s
of 3.5 and 2.1 mg/kg, respectively, demonstrated good
efficacy,
while minocycline was not therapeutically effective at doses
of
up to 32 mg/kg. Intravenous administration of TBG-MINO or
DMG-DMDOT
resulted in good efficacy against an infection caused
by
E. coli UBMS 88-1, a strain carrying the
tet(B) efflux resistance determinant,
while minocycline was
not efficacious. Both TBG-MINO and DMG-DMDOT
showed efficacy
(ED
50s,
2.0 mg/kg) against an infection caused
by a
minocycline-resistant
E. coli clinical isolate (NEMC
87-30).
| |
DISCUSSION |
Previous studies (5, 9, 12, 22, 31, 33, 34)
demonstrated that the DMG modification of the 9 position of the tetracycline molecule (29), i.e., DMG-MINO and DMG DMDOT,
resulted in drugs that have the ability to overcome the two major
mechanisms responsible for tetracycline resistance, i.e., ribosomal
protection or active efflux of drug out of the bacterial cell (1,
2, 13-15, 24, 26, 27). TBG-MINO, the
9-t-butylglycylamido derivative of minocycline, a
recently synthesized member of the glycylcycline family of
compounds, possesses a spectrum of activity similar to those DMG-MINO
and DMG-DMDOT against most of the strains carrying the
tetracycline resistance determinants. However, TBG-MINO has improved in
vitro and in vivo activities against E. coli strains carrying the tet(A) or tet(C) resistance determinant.
The activity of TBG-MINO matched the activities of DMG-MINO and
DMG-DMDOT against recent clinical gram-negative and
-positive aerobic and anaerobic isolates, including minocycline- and
tetracycline-resistant isolates. Differences in activities between
TBG-MINO, DMG-MINO, and DMG-DMDOT were noted against some
strains of E. coli, against which TBG-MINO was
more active than DMG-MINO or DMG-DMDOT. Because TBG-MINO
demonstrated better activity when it was tested against prototype strains of E. coli with
tet(A) or tet(C) resistance determinants, it is
possible that some of these clinical isolates may contain one or both
of these resistance determinants. The MIC90s of
TBG-MINO for MRSA and methicillin-resistant coagulase-negative staphylococci were also lower. The MICs of DMG-DMDOT and
DMG-MINO were elevated for two of the clinical MRSA strains, which
contained both tet(K) and tet(M) resistance
determinants, but these strains were more sensitive to TBG-MINO
(data not shown). Because all three glycylcyclines showed good
activities against tet(M)-carrying strains, the slightly
improved activity of TBG-MINO might reflect the slightly better
inherent activity noted against tet(K)-containing strains. TBG-MINO and DMG-MINO were less active than
DMG-DMDOT against Proteus spp. and
M. morganii.
The improved in vitro activity of TBG-MINO was also observed in
vivo when its activity against acute lethal infections in mice was
tested. When it was dosed intravenously, TBG-MINO was as
effective as minocycline against infections caused by
minocycline-susceptible bacteria including MRSA and
tet(K)-containing S. aureus.
However, the ED50s of TBG-MINO and DMG-DMDOT
against infections caused by MRSA that also contained tet(M)
were lower than those of minocycline. Infections caused by
E. coli strains carrying tet(A),
tet(B), tet(C), or tet(M) were more
responsive to treatment with TBG-MINO or DMG-DMDOT than to
treatment with minocycline. The activity of TBG-MINO, however, exceeded
the activity of DMG-DMDOT against infections caused by the
tet(A)- and tet(C)-containing strains, thus
reflecting the improved in vitro activity of TBG-MINO over that
of DMG-DMDOT. Both TBG-MINO and DMG-DMDOT had poor
efficacies when they were administered orally.
The ability of TBG-MINO to overcome the major tetracycline resistance
mechanisms and extend its spectrum of activity to include multidrug-resistant staphylococci, penicillin-resistant S. pneumoniae, vancomycin-resistant enterococci, anaerobes, and
minocycline-resistant bacteria while retaining activity against
minocycline-susceptible microorganisms makes it an attractive new
antibacterial agent. Resistance among S. pneumoniae,
Enterococcus spp., and MRSA is becoming an increasing
medical problem worldwide (10, 11, 17, 18, 19, 23, 32), with
reduced therapeutic options and an increased need for new
antimicrobial agents. TBG-MINO at concentrations of 0.5
µg/ml inhibited all strains of penicillin-resistant S. pneumoniae, vancomycin-resistant
Enterococcus spp., and MRSA. Therefore, additional
evaluation of TBG-MINO is warranted.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Wyeth-Ayerst
Research, 401 N. Middletown Rd., Pearl River, NY 10965. Phone: (914)
732-3070. Fax: (914) 732-5671. E-mail:
petersp{at}war.wyeth.com.
| |
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Antimicrobial Agents and Chemotherapy, April 1999, p. 738-744, Vol. 43, No. 4
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Abstract
Introduction
