molecules of the month

Overview. A common route of resistance to tuberculosis involves Mtb erm37 expression, which expresses an RNA methyltransferase that methylates the A2058 position of the 23S ribosome RNA, hindering macrolide antibiotic binding. The sequanamycins (SEQs) are a class of molecules that overcomes this resistance mechanism, primarily attributed to the change from a dimethylamine to a carbonyl/oxime, which appears to compensate for the change in a key water molecule lacking in the mutant. Key to improving oral bioavailability and overall PK were the increase in acid and liver stability through use of an uncommon 1,4-oxazepane. The oral efficacy of the molecule is remarkable given its beyond the rule of 5 (bRo5) properties. SEQs overcome a well-known RNA-based resistance mechanism in Mycobacterium tuberculosis…