The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome

Abstract

Omadacycline is an aminomethylcycline antibiotic with potent activity against many Gram-positive and Gram-negative pathogens, including strains carrying the major efflux and ribosome protection resistance determinants. This makes it a promising candidate for therapy of severe infectious diseases. Omadacycline inhibits bacterial protein biosynthesis and competes with tetracycline for binding to the ribosome. Its interactions with the 70S ribosome were, therefore, analyzed in great detail and compared with tigecycline and tetracycline. All three antibiotics are inhibited by mutations in the 16S rRNA that mediate resistance to tetracycline in Brachyspira hyodysenteriae, Helicobacter pylori, Mycoplasma hominis, and Propionibacterium acnes. Chemical probing with dimethyl sulfate and Fenton cleavage with iron(II)-complexes of the tetracycline derivatives revealed that each antibiotic interacts in an idiosyncratic manner with the ribosome. X-ray crystallography had previously revealed one primary binding site for tetracycline on the ribosome and up to five secondary sites. All tetracyclines analyzed here interact with the primary site and tetracycline also with two secondary sites. In addition, each derivative displays a unique set of non-specific interactions with the 16S rRNA.

Omadacycline Enters the Ring: A New Antimicrobial Contender

“…The two major mechanisms of resistance are increased number of efflux pumps and production of ribosomal protection proteins. The two minor mechanisms of resistance include modification of the ribosomal target and enzymatic inactivation . Omadacycline retains activity for organisms with these resistance genes and does not appear to be affected by resistance to other antimicrobials .…”

“…In addition to evading the mechanisms of resistance above, the resistance mechanisms active against omadacycline have not been found to be clinically relevant . An analysis on omadacycline binding sites was performed on E. coli isolates.…”

“…Two mutations to the 16S rRNA are required to affect the primary binding site, but when these mutations occur, tetracycline resistance results in a 4‐ to 8‐fold increase in MIC. However, this mechanism causes low level resistance and decreases the fitness of the organisms by impairing cell growth …”

“…Tetracycline resistance is common in both grampositive and gram-negative organisms 10,15 The resistance mechanisms against tetracyclines can be stratified based on frequency into major and minor mechanisms. 6,7,16 The two major mechanisms of resistance are increased number of efflux pumps and production of ribosomal protection proteins. The two minor mechanisms of resistance include modification of the ribosomal target and enzymatic inactivation.…”

“…The two minor mechanisms of resistance include modification of the ribosomal target and enzymatic inactivation. 6,7,16 Omadacycline retains activity for organisms with these resistance genes and does not appear to be affected by resistance to other antimicrobials. 7,8,10 No strains with induced resistance have been reported.…”