In Vitro Profiling of the Synthetic RNA Polymerase Inhibitor MMV688845 against Mycobacterium abscessus

Abstract

ABSTRACT 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.

Keywords

• M. abscessus
• MMV688845
• RNA polymerase
• drug development
• nontuberculous mycobacteria