Todd Bowser

Laura Honeyman; Mohamed A. Ismail; Mark L. Nelson; Beena Bhatia; Todd Bowser; Jackson Chen; Rachid Mechiche; Kwasi Ohemeng; Atul K. Verma; E. Pat Cannon; Ann Macone; S. Ken Tanaka; Stuart B. Levy

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).

David E. Cane; Todd Bowser

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.

Stuart B. Levy; Michael N. Alekshun; Brent L. Podlogar; Kwasi Ohemeng; Atul K. Verma; Tadeusz Warchol; Beena Bhatia; Todd Bowser; Mark Grier

Mark L. Nelson; Roger Frechette; Peter Viski; Mohamed Y. Ismail; Todd Bowser; Laura Mcintyre; Beena Bhatia; Paul Hawkins; Laxma Reddy; Karen Stapleton; Tadeusz Warchol; Paul Sheahan

Mark L. Nelson; Roger Frechette; Peter Viski; Mohamed Y. Ismail; Todd Bowser; Jimmy Dumornay; Glen Rennie; Gui Liu; Darrell J. Koza; Paul Sheahan; Karen Stapleton; Paul Hawkins; Beena Bhatia; Atul K. Verma; Laura Mcintyre; Tadeusz Warchol; David Messersmith

Mark L. Nelson; Roger Frechette; Peter Viski; Mohamed A. Ismail; Todd Bowser; Beena Bhatia; David Messersmith; Laura Mcintyre; Darrell Koza; Glen Rennie; Paul Sheahan; Paul Hawkins; Atul Verma; Tadeusz Warchol; Upul K. Bandarage

Todd Bowser; Victoria J. Bartlett; Mark Grier; Atul K. Verma; Taduesz Warchol; Stuart B. Levy; Michael N. Alekshun

Mark L. Nelson; Kwasi Ohemeng; Roger Frechette; Mohamed Y. Ismail; Laura Honeyman; Todd Bowser; Paul Abato; Victor Amoo; Haregewein Assefa; Joel Berniac; Beena Bhatia; Jackson Chen; Oak K. Kim; Rachid Mechiche; N. Laxma Reddy; Atul K. Verma; Peter Viski; Tadeusz Warchol; Ivan Yanachkov

Mark L. Nelson; Roger Frechette; Mohamed Y. Ismail; Laura Honeyman; Todd Bowser; Beena Bhatia

Victor Amoo; Haregewein Assefa; Beena Bhatia; Joel Berniac; Todd Bowser; Jackson Chen; Mark Grier; Laura Honeyman; Oak K. Kim; Rachid Mechiche; Kwasi Ohemeng; Jingwen Pan