Todd Bowser

Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline

ABSTRACT A series of novel tetracycline derivatives were synthesized with the goal of creating new antibiotics that would be unaffected by the known tetracycline resistance mechanisms. New C-9-position derivatives of minocycline (the aminomethylcyclines [AMCs]) were tested for in vitro activity against Gram-positive strains containing known tetracycline resistance mechanisms of ribosomal protection (Tet M in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) and efflux (Tet K in S. aureus and Tet L in E. faecalis). A number of aminomethylcyclines with potent in vitro activity (MIC range of ≤0.06 to 2.0 μg/ml) were identified. These novel tetracyclines were more active against one or more of the resistant strains than the reference antibiotics tested (MIC range, 16 to 64 μg/ml). The AMC derivatives were active against bacteria resistant to tetracycline by both efflux and ribosomal protection mechanisms. This study identified the AMCs as a novel class of antibiotics evolved from tetracycline that exhibit potent activity in vitro against tetracycline-resistant Gram-positive bacteria, including pathogenic strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). One derivative, 9-neopentylaminomethylminocycline (generic name omadacycline), was identified and is currently in human trials for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

Trichodiene synthase: Mechanism-based inhibition of a sesquiterpene cyclase

The 10-cyclopropylidene analog of farnesyl diphosphate was shown to be a mechanism-based inhibitor of trichodiene synthase with an inactivation rate (k(inact)) of 0.010 +/- 0.0003 min(-1) and an apparent Ki of 663 +/- 75 nM. The presence of three anomalous sesquiterpene products detected in incubation mixtures indicate that the compound also serves as a substrate of the enzyme.