In a library screen of
tuberculosis-active compounds for anti-Mycobacterium abscessus activity, we previously identified the synthetic
phenylalanine amide MMV688845. In Mycobacterium tuberculosis, this class was shown to target the RpoB subunit of
RNA polymerase, engaging a binding site distinct from that of the
rifamycins. Due to its bactericidal activity,
rifampicin is a key
drug for the treatment of
tuberculosis (TB). However, this
natural product shows poor potency against M. abscessus due to enzymatic modification, and its clinical use is limited. Here, we carried out in vitro microbiological profiling of
MMV688845 to determine its attractiveness as a substrate for a chemistry optimization project.
MMV688845 was broadly active against the M. abscessus complex, displayed bactericidal against M. abscessus in vitro, and in a macrophage
infection model showed additivity with commonly used anti-M. abscessus
antibiotics and synergy with
macrolides. Analyses of spontaneous resistant mutants mapped resistance to RpoB, confirming that
MMV688845 has retained its target in M. abscessus. Together with its chemical tractability, the presented microbiological profiling reveals
MMV688845 as an attractive starting point for hit-to-lead development to improve potency and to identify a lead compound with demonstrated oral in vivo efficacy. IMPORTANCE
Infections with nontuberculous mycobacteria are an increasing health problem, and only a few new
drug classes show activity against these multidrug-resistant bacteria. Due to insufficient
therapy options, the development of new
drug leads is necessary and should be advanced. The lead compound
MMV688845, a substance active against M. abscessus complex, was characterized in depth. In various assays, it showed activity against M. abscessus, synergy with other
antibiotics, and bactericidal effects.