Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic.

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Grossman TH, Starosta AL, Fyfe C, O'Brien W, Rothstein DM, Mikolajka A, Wilson DN, Sutcliffe JA

Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic.

Antimicrob Agents Chemother. 2012 May;56(5):2559-64. doi: 10.1128/AAC.06187-11. Epub 2012 Feb 21.

PubMed ID

22354310 [ View in PubMed

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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 mug/ml) was unaffected by tet(M), tet(K), and tet(B) and increased to 0.25 and 4 mug/ml in the presence of tet(A) and tet(X), respectively. Tetracycline, in contrast, was significantly less potent (MIC >/= 128 mug/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 mug/ml) and [(3)H]tetracycline ribosome-binding competition (IC(50) = 0.22 +/- 0.07 muM) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Eravacycline	30S ribosomal protein S4	Protein	Escherichia coli (strain K12)	Yes	Inhibitor	Details