Target- and Resistance-Based Mechanistic Studies with TP-434, a Novel Fluorocycline Antibiotic
- 1 May 2012
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 56 (5), 2559-2564
- https://doi.org/10.1128/aac.06187-11
Abstract
TP-434 is a novel, broad-spectrum fluorocycline antibiotic with activity against bacteria expressing major antibiotic resistance mechanisms, including tetracycline-specific efflux and ribosomal protection. The mechanism of action of TP-434 was assessed using both cell-based and in vitro assays. In Escherichia coli cells expressing recombinant tetracycline resistance genes, the MIC of TP-434 (0.063 μg/ml) was unaffected by tet (M), tet (K), and tet (B) and increased to 0.25 and 4 μg/ml in the presence of tet (A) and tet (X), respectively. Tetracycline, in contrast, was significantly less potent (MIC ≥ 128 μg/ml) against E. coli cells when any of these resistance mechanisms were present. TP-434 showed potent inhibition in E. coli in vitro transcription/translation (50% inhibitory concentration [IC 50 ] = 0.29 ± 0.09 μg/ml) and [ 3 H]tetracycline ribosome-binding competition (IC 50 = 0.22 ± 0.07 μM) assays. The antibacterial potencies of TP-434 and all other tetracycline class antibiotics tested were reduced by 4- to 16-fold, compared to that of the wild-type control strain, against Propionibacterium acnes strains carrying a 16S rRNA mutation, G1058C, a modification that changes the conformation of the primary binding site of tetracycline in the ribosome. Taken together, the findings support the idea that TP-434, like other tetracyclines, binds the ribosome and inhibits protein synthesis and that this activity is largely unaffected by the common tetracycline resistance mechanisms.Keywords
This publication has 40 references indexed in Scilit:
- Antibiotics in development targeting protein synthesisAnnals of the New York Academy of Sciences, 2011
- Differential Effects of Thiopeptide and Orthosomycin Antibiotics on Translational GTPasesCell Chemical Biology, 2011
- Antibiotics in the clinical pipeline in 2011The Journal of Antibiotics, 2011
- The 10 × ‘20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020Clinical Infectious Diseases, 2010
- Combined ramR Mutation and Presence of a Tn 1721 -Associated tet (A) Variant in a Clinical Isolate of Salmonella enterica Serovar Hadar Resistant to TigecyclineAntimicrobial Agents and Chemotherapy, 2010
- Sphingobacteriumsp. strain PM2-P1-29 harbours a functionaltet(X) gene encoding for the degradation of tetracyclineJournal of Applied Microbiology, 2009
- Antipropionibacterial Activity of BAL19403, a Novel Macrolide AntibioticAntimicrobial Agents and Chemotherapy, 2007
- Differential pharmacology of atypical antipsychotics: Clinical implicationsAmerican Journal of Health-System Pharmacy, 2007
- Functional, Biophysical, and Structural Bases for Antibacterial Activity of TigecyclineAntimicrobial Agents and Chemotherapy, 2006
- Mutations in the Interdomain Loop Region of thetetA(A) Tetracycline Resistance Gene Increase Efflux of Minocycline and GlycylcyclinesMicrobial Drug Resistance, 2000