In vitro antibacterial activity of trospectomycin (U-63366F), a novel spectinomycin analog

Abstract

Trospectomycin (U-63366F) is a novel spectinomycin analog with broad-spectrum antibacterial activity. The in vitro activity of this analog was compared with that of spectinomycin and other reference antibiotics against 411 clinical isolates of aerobic and anaerobic bacteria. MICs were determined by agar or broth dilution methods. The stability of trospectomycin in the presence of an enzyme extract derived from spectinomycinresistant Escherichia coli was determined. Trospectomycin was more active than spectinomycin (4-to 32-fold) against strains of numerous bacterial species, including staphylococci, streptococci, Haemophilus influenzae, Branhamella catarrhalis, Neisseria gonorrhoeae, Proteus species, Bacteroides species, Clostridium difficile, Clostridium species, and Chlamydia trachomatis. Trospectomycin demonstrated a moderate level of activity (comparable to that of spectinomycin) for most species of the family Enterobacteriaceae tested and was generally cross resistant with spectinomycin. Trospectomycin was susceptible to inactivation by crude enzyme preparations from spectinomycin-inactivating strains of E. coli. Trospectomycin inhibited a variety of clinically important organisms, including agents of sexually transmitted diseases and pelvic inflammatory disease. Clinical studies with this novel aminocyclitol antibiotic are in progress.Spectinomycin is an aminocyclitol antibiotic with broadspectrum antibacterial activity (9). Spectinomycin is not an aminoglycosidic aminocyclitol and has never exhibited the oto-or nephrotoxicity associated with that antibiotic group (15, 16). The antibiotic achieves high levels in animal and human serum and urine and has been used successfully to treat a variety of infections (10, 24). However, it is generally less active in vitro than the aminoglycosides and has been used primarily for the treatment of uncomplicated anogenital gonorrhea, including penicillin-resistant gonorrhea (17). Spectinomycin is not indicated for the treatment of infections due to Chlamydia trachomatis or Treponema pallidum.Chemical analogs of spectinomycin were prepared in an attempt to enhance the potency of spectinomycin or expand its antimicrobial spectrum. Structural changes in the cyclitol portion (A-ring; Fig. 1) of the molecule result in a loss of bioactivity (18). Synthetic methods developed in The Upjohn Company laboratories have afforded the opportunity to modify the previously inaccessible C-ring portion of the molecule to yield 3'-and 6'-modified spectinomycin analogs (22,28 177, 1982). The 6' analogs are generally superior in antimicrobial activity to the 3' analogs. When compared with spectinomycin in vivo, the 6' analogs are 2-to 50-fold more potent than spectinomycin against Haemophilus influenzae, Streptococcus pyogenes, and Salmonella spp. (C. W. Ford, J. C. Osinski, G. E. Zurenko, and R. J. Yancey, Jr., 22nd ICAAC, abstr. no. 178, 1982). Of the analogs tested, 6' propylspectinomycin sulfate pentahydrate (trospectomycin sulfate or U-63366F) (Fig. 1) has been judged to possess the gr...

In vitro susceptibilities of oral pigmented Bacteroides species to trospectomycin and other selected antimicrobial agents

“…In comparison to the parent molecule, trospectomycin has an expanded antimicrobial spectrum and enhanced potency (11). It has excellent in vitro activity against most gram-positive cocci, as well as against Haemophilus influenzae, Haemophilus ducreyi, Neisseria gonorrhoeae (both P-lactamase-positive and -negative strains), Mycoplasma species, and Chlamydia trachomatis (8, 267,1987).…”

Antibacterial activity of trospectomycin (U-63366F) and initial evaluations of disk diffusion susceptibility tests

“…264,1987). The in vitro activity of trospectomycin has been reported to be superior to that of spectinomycin (5,8,9). Both aminocyclitol antibiotics function by binding to 30S ribosomal subunits, thus inhibiting protein synthesis (A. L. Laborde and R. J. Mourey, 27th ICAAC, abstr.…”

Human safety and pharmacokinetics of a single intramuscular dose of a novel spectinomycin analog, trospectomycin (U-63,366F)

“…Trospectomycin sulfate (U-63,366F; trospectomycin), an analog of spectinomycin, is crystalline and water soluble (17,18) and has demonstrated in vitro activity against anaerobic bacteria and against gram-positive and some gram-negative aerobic bacteria including Chlamydia trachomatis (20,21). Trospectomycin is 8 to 10 times more active than spectinomycin and has activity against a spectrum of pathogenic species including species from the genera Staphylococcus, Streptococcus, Haemophilus, Gardnerella, Neisseria, Peptococcus, Peptostreptococcus, Bacteroides, Mobiluncus, Chlamydia, Mycoplasma, and Ureaplasma (5,12,19).…”