Affiliation:
1. Infectious Disease Research Section, Wyeth-Ayerst Research, Pearl River, New York 10965
Abstract
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 [ED
50
s], 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) (ED
50
s, 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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