In Vitro and In Vivo Antibacterial Activities of a Novel Glycylcycline, the 9- t -Butylglycylamido Derivative of Minocycline (GAR-936)

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, theN,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, andStreptococcus pneumoniae isolates. TBG-MINO, administered intravenously, demonstrated efficacy against infections caused byS. aureus including MRSA strains and strains containingtet(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 asE. coli strains containing either tet(M) or the efflux determinant tet(A), tet(B), ortet(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.

Therapeutic options for the treatment of infections with multiresistant grampositive bacteria in oncological patients

“…As a derivative of tetracyclines, it acts bacteriostatically via inhibition of bacterial protein synthesis by reversible binding to the 30S ribosomal subunit [15]. By chemical modifi cation it overcomes typical causes of tetracycline resistance, such as effl ux pumps and ribosomal protection mechanisms [16]. Th us, it features a very broad antimicrobial spectrum including MRSA, VRE, penicillin-resistant S. pneumoniae as well as many gramnegative and anaerobic species.…”

History of Industrial Biotechnology

“…A semi -synthetic tetracycline, that is, a glycylcycline, was successfully developed for use against tetracycline -resistant bacteria [62] . The 9 -t -butylglycylamido derivative of minocycline called tigecycline, was active against resistant Gram -positive, Gram -negative, and anaerobic bacteria possessing the ribosomal protection resistance mechanism or the active effl ux mechanism.…”

Multidrug-resistant pathogens: Mechanisms of resistance and epidemiology

“…All pneumococci are susceptible to vancomycin, and many isolates in the United States are susceptible to clindamycin (only 3.7% of isolates are resistant) [4]. Penicillin-resistant pneumococci are susceptible, in vitro, to quinupristin/dalfopristin (a combination streptogramin antibiotic) [4], linezolid (a member of the oxazolidinone class that functions as a ribosomal inhibitor) [ ment, such as HMR 3647 (a ketolide) [9], members of the glycylcycline class of antibiotics [10], and everninomicin (an oligosaccharide) [11].…”