In vitro activity of a novel aminomethylcycline antibacterial (KBP-7072), a third-generation tetracycline, against clinical isolates with molecularly characterized tetracycline resistance mechanisms

Abstract

Objectives This study evaluated the in vitro activity of KBP-7072 against 413 contemporary surveillance isolates, including subsets with known tetracycline resistance genes. Materials In total, 105 Klebsiella pneumoniae (51 tetracycline resistant), 103 Escherichia coli (52 tetracycline resistant), 103 Staphylococcus aureus (51 tetracycline resistant) and 102 Streptococcus pneumoniae (51 tetracycline resistant) isolates were included. These isolates were tested by broth microdilution using fresh media. CLSI/EUCAST breakpoints were applied, except for tigecycline and omadacycline, which used FDA criteria. Results KBP-7072 (MIC50, 0.06 mg/L), tigecycline (MIC50, 0.12 and 0.25 mg/L) and omadacycline (MIC50, 0.12 and 0.5 mg/L) showed similar MIC50s for tetracycline-susceptible and -resistant S. aureus. Other tetracycline comparators had their MIC50 increased 64- to 256-fold by tet. For S. pneumoniae, KBP-7072 (MIC50/90, ≤0.015/0.03 mg/L) showed the lowest MICs, which remained unchanged for tetracycline-susceptible or -resistant isolates [mostly tet(M)]. Similar MICs were observed for omadacycline (MIC50/90, 0.03–0.06/0.06 mg/L) and tigecycline (MIC50/90, 0.03/0.03 mg/L) in the S. pneumoniae population. Tetracycline-susceptible and -resistant E. coli [94.2% tet(A)/tet(B)], KBP-7072 (MIC90, 0.25 and 1 mg/L, respectively) and tigecycline (MIC90, 0.25 and 0.5 mg/L) showed similar MIC90s. KBP-7072 (MIC50/90, 0.25/0.5 mg/L) and tigecycline (MIC50/90, 0.5/0.5 mg/L) had the lowest MIC for tetracycline-susceptible K. pneumoniae. The MIC for KBP-7072 (MIC50/90, 1/4 mg/L) and tigecycline (MIC50/90, 1/2 mg/L) increased 2- to 8-fold for tetracycline-resistant K. pneumoniae, which mostly produced Tet(A). Conclusions KBP-7072 activity was minimally affected by the presence of acquired tetracycline genes.

Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

“…The aminomethylcycline KBP‐7072 (phase 1, oral) is a third‐generation tetracyclin with good in vitro activities against Gram‐positive bacteria, Enterobacteriaceae and other Enterobacterales, and A. baumannii (Huband et al , 2022 ). Moreover, acquired resistance genes against other tetracyclins seem to have only a minimal effect on KBP‐7072 (Pfaller et al , 2021 ).…”

Antibiotics in the clinical pipeline as of December 2022

“…Zifanocycline ( 45 ) (KBP-7072; IV/po) is a tetracycline derivative (aminomethylcycline) being developed by KBP BioSciences (Princeton, NJ, USA) that has completed three phase-I trials (NCT02454361, NCT02654626, and NCT04532957) and is currently being evaluated in another phase-I trial (NCT05507463). Zifanocycline ( 45 ) has broad spectrum antibacterial activity [ 251 – 253 ] and a preprint has disclosed an X-ray structure of 45 bound to the Thermus thermophilus 30 S ribosomal subunit [ 254 ]. As with CRS3123 ( 28 ), zifanocycline ( 45 ) was listed as discontinued or halted in the previous review [ 23 ].…”