Analogue of the natural product ecumicin causes sustained growth inhibition of Mycobacterium tuberculosis under multiple growth conditions

Abstract

Multi-drug-resistant Mycobacterium tuberculosis is an escalating global health problem, and a strong pipeline of novel compounds is needed to combat rising antimicrobial resistance. Ecumicin is a novel analogue of the natural antimycobacterial cyclic peptide ecumicin, with selective activity against Mycobacterium species. The activity of ecumicin∗ was compared to that of frontline tuberculosis therapies under in vitro conditions representative of niches where M. tuberculosis resides in the human lung. M. tuberculosis expressing luciferase was cultured in defined 7H9-based media containing glucose, butyrate, valerate, acidified glucose, low or high cholesterol concentrations, or intracellularly in human THP-1 and mouse RAW264.7 macrophages. Ecumicin∗ effectively killed M. tuberculosis under all assay conditions. The IC₉₀ of ecumicin∗ was increased in acidified 7H9 media, and both IC₉₀ and AUC₉₀ values were increased in valerate, cholesterol, high cholesterol culture media. In time-kill assays, anti-M. tuberculosis activity of ecumicin∗ was sustained for 28 days. By comparison, IC₅₀ and IC₉₀ of isoniazid were decreased in butyrate and cholesterols medias, and mycobacterial regrowth occurred in glucose and cholesterol culture medias within 14 days at high isoniazid concentrations. Ecumicin∗ inhibited M. tuberculosis growth in THP-1 macrophages, and at higher IC₉₀ in mouse RAW264.7 macrophages. Drug testing under disease-relevant conditions is important prior to in vivo examination, and ecumicin∗ has proven effective in multiple in vitro conditions typical of the lung environment of tuberculosis patients.