The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Bacillus anthracis Infection in BALB/c Mice and Cynomolgus Macaques

Abstract

The fluorocycline TP-271 was evaluated in mouse and nonhuman primate (NHP) models of inhalational anthrax. BALB/c mice were exposed by nose-only aerosol to Ames spores at a level of 18 to 88 lethal doses sufficient to kill 50% of exposed individuals (LD). When 21 days of once-daily dosing was initiated at 24 h postchallenge (the postexposure prophylaxis [PEP] study), the rates of survival for the groups treated with TP-271 at 3, 6, 12, and 18 mg/kg of body weight were 90%, 95%, 95%, and 84%, respectively. When 21 days of dosing was initiated at 48 h postchallenge (the treatment [Tx] study), the rates of survival for the groups treated with TP-271 at 6, 12, and 18 mg/kg TP-271 were 100%, 91%, and 81%, respectively. No deaths of TP-271-treated mice occurred during the 39-day posttreatment observation period. In the NHP model, cynomolgus macaques received an average dose of 197 LD of Ames spore equivalents using a head-only inhalation exposure chamber, and once-daily treatment of 1 mg/kg TP-271 lasting for 14 or 21 days was initiated within 3 h of detection of protective antigen (PA) in the blood. No (0/8) animals in the vehicle control-treated group survived, whereas all 8 infected macaques treated for 21 days and 4 of 6 macaques in the 14-day treatment group survived to the end of the study (56 days postchallenge). All survivors developed toxin-neutralizing and anti-PA IgG antibodies, indicating an immunologic response. On the basis of the results obtained with the mouse and NHP models, TP-271 shows promise as a countermeasure for the treatment of inhalational anthrax.

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

“…In the present study, TP-271 was active in vitro against F. tularensis, a pathogen that could be used as a bioweapon during a terrorist attack. Furthermore, TP-271 was previously shown to be efficacious in mouse models of plague and anthrax, supporting the possibility that TP-271 could be used as a broad-spectrum medical countermeasure if results in mice translate to larger animal models representative of human disease (20,21).…”

Nonhuman primate species as models of human bacterial sepsis

“…Similar findings were seen in baboons infused with B. anthracis -derived peptidoglycan, the predominant carbohydrate of the Gram-positive bacterial cell wall, indicating this molecule is a pathogen-associated molecular pattern (PAMP) likely responsible for the inflammation and hypercoagulability seen with clinical anthrax infection 87 . Other studies using rhesus or cynomolgus macaques administered aerosolized B. anthracis spores via nose- or head-only exposure chambers 88–90 . Animals developed a moribund, disseminated anthrax infection with sepsis and respiratory failure over several days 88,89 .…”

“…Other studies using rhesus or cynomolgus macaques administered aerosolized B. anthracis spores via nose- or head-only exposure chambers 88–90 . Animals developed a moribund, disseminated anthrax infection with sepsis and respiratory failure over several days 88,89 . The inhalational model mimics the likely mechanism of exposure to B. anthracis (airborne dispersion) in a possible terrorist attack and is therefore invaluable to researchers developing novel anthrax therapies for such a public health emergency 90,91 .…”

“…The macaque anthrax model has also been used to develop novel anthrax therapies. Cynomolgus macaques inoculated with nebulized B. anthracis experienced significantly improved survival after receiving the novel tetracycline class antibiotic TP-271 88 . Survival of inhalational anthrax in this primate species was also significantly improved by administering a post-exposure prophylaxis vaccine, AV7909 89 .…”

Translational control of antibiotic resistance

“…Of the royalsocietypublishing.org/journal/rsob Open Biol. 9: 190051 fluorocyclines, TP-271, TP-6076 and eravacycline have displayed potent in vivo efficacy, and eravacycline was FDA approved in 2018 [64,[74][75][76][77][78]. These drugs have also been shown to be effective in vitro against tetracycline-resistant clinical isolates, including isolates that are known to maintain ribosomal protection proteins [76,78].…”