Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline.
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).
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Laura
L
Honeyman
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Mohamed
M
Ismail
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Mark L
ML
Nelson
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Beena
B
Bhatia
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Todd E
TE
Bowser
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Jackson
J
Chen
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Rachid
R
Mechiche
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Kwasi
K
Ohemeng
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Atul K
AK
Verma
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
E Pat
EP
Cannon
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Ann
A
Macone
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA ktanaka@paratekpharm.com.
S Ken
SK
Tanaka
Paratek Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Stuart
S
Levy
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000494:pharmacology*; D065507:Vancomycin-Resistant Enterococci / Q000187:drug effects
D000900:Anti-Bacterial Agents; D013754:Tetracyclines; C000591640:omadacycline; D008911:Minocycline