Benn, V. | Search bioRxiv

bioRxiv2020

In Vivo Efficacy and PK/PD Modeling of KBP-7072, An Aminomethylcycline Antibiotic, in Neutropenic Pneumonia and Thigh Infection Models

KBP-7072 is a novel aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative multidrug resistant bacterial isolates and strains. Antibacterial activity and the PK/PD relationship were assessed using in vivo infection models. Six to 8-week-old female CD-1 mice were randomized to oral KBP-7072, minocycline and vehicle in a Klebsiella pneumoniae murine model, and KBP-7072, linezolid and vehicle for a Streptococcus pneumoniae murine model. Each animal was inoculated with K. pneumoniae or S. pneumoniae placed on the tip of the nares. KBP-7072 and antibiotics were started 3 hours post inoculation and continued for 3 days for K. pneumoniae, and were started 18 hours post inoculation and continued for 3 days for S. pneumoniae. Animals were euthanized at 0 (control group), 24, 48 or 72 hours post final dose. In vivo efficacy and PK/PD parameters were determined in Staphylococcus aureus isolate (6424MRSA-363), K. pneumoniae isolate (6680kpn-522), and E. coli isolate (6691eco-558) murine thigh infection models. In vivo efficacy and PK/PD parameters (fAUC/MIC, fCmax/MIC and %T>MICfree) were calculated. Respiratory infection occurred in all inoculated mice. KBP-7072 produced a significant (p<0.05 to <0.001) dose-dependent decrease in colony forming units (CFUs) at all doses and a dose-dependent increase in survival rate (p<0.001 vs. vehicle). The median survival in all KBP-7072-treated groups was significantly greater vs. comparators (p<0.001). These results demonstrate potent in vivo efficacy for KBP-7072 and determined that the AUC/MIC parameter was optimal for assessing bacteriostatic and bactericidal effects of KBP-7072.

pharmacology and toxicology↗

bioRxiv2018

The third-generation tetracycline, KBP-7072, exploits and reveals a new potential of the primary tetracycline binding pocket

Antibiotic resistance is a growing threat to human health requiring the discovery or development of new anti-infectives. As such, KBP-7072 is a novel tetracycline derivative that exhibits broad-spectrum activity against Gram-positive and -negative bacterial strains. To determine the mechanism of action of KBP-7072 and understand how its unique C9 extension can be used to combat the growing problem of antibiotic resistance we determined the structure of KBP-7072 bound to the bacterial 30S ribosomal subunit, the inhibitory target of typical tetracyclines. We show that KBP-7072 binds to the primary tetracycline binding site on the 30S ribosomal subunit consistent with it acting as a protein synthesis inhibitor that blocks A-site occupation. Moreover, the unique chemical nature of KBP-7072{acute}s C9 extension leads to a distinctive interaction pattern with the 30S subunit that distinguishes KBP-7072 from the third-generation tetracycline, Tigecycline, and thus expands the interaction potential of the primary tetracycline binding pocket.

biochemistry↗