In Vitro Activity of Bedaquiline against Nontuberculous Mycobacteria in China

Abstract

The main goal of our study was to evaluate the in vitro bedaquiline susceptibility of six prevalent species of pathogenic nontuberculous mycobacteria (NTM) in China. In addition, we investigated the potential molecular mechanisms contributing to bedaquiline resistance in the different NTM species. Among slowly growing mycobacteria (SGM), bedaquiline exhibited the highest activity against 44 (20.2%), 42 (25.8%), and 7 (31.8%), respectively, were resistant to bedaquiline. No significant differences in the proportions of bedaquiline resistance among these species were observed (P Ͼ 0.05). Genetic mutations were observed in 74 isolates (10.8%), with all nucleotide substitutions being synonymous. In conclusion, our data demonstrate that bedaquiline shows moderate in vitro activity against NTM species. Using the proposed ECOFF values, we could distinguish between bedaquiline-resistant and -susceptible strains with the broth dilution method. In addition, no nonsynonymous mutations in the atpE gene that conferred bedaquiline resistance in all six NTM species were identified.

In Vitro Activities of Bedaquiline and Delamanid against Nontuberculous Mycobacteria Isolated in Beijing, China

“…Bdq also exhibited very good inhibitory activities against most of the tested clinical SGM isolates, especially the most prevalent and highly pathogenic species, such as M. kansasii and Mycobacterium avium complex (MAC), as previously described (10). Pang et al also demonstrated that Bdq had good inhibitory activities against clinical strains of some SGM species isolated from China (9). All the tested NTM isolates in this study were collected in four hospitals located in mideastern China from 2011 to 2015, while the NTM isolates in our study were collected in Beijing Chest Hospital located in northern China from 2015 to 2016.…”

“…Furthermore, we also evaluated the activity of Bdq and Dlm against 52 reference strains of different mycobacterium species to gain insights on their potential use for specific NTM species. As they are new drugs, well-recognized susceptibility testing methods for Bdq and Dlm have not been developed, and breakpoints to define drug resistance for them have never been discussed prudently (9,10). Defining the ECOFF value based on data produced by multiple centers with a large number of strains is an important step to establish the breakpoints.…”

“…All the 209 NTM clinical strains were isolated from tuberculosis-suspected patients. The strains were classified as NTM preliminarily with p-nitrobenzoic acid-containing medium and then were differentiated into species level by 16S rRNA, hsp65, rpoB, and 16-23S rRNA internal transcribed spacer sequencing (9). All the isolates were stored at Ϫ80°C and subcultured on Lowenstein-Jensen (LJ) medium before performing the microplate alamarBlue assay (MABA).…”

“…Bdq is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent MICs for some NTM species (2,9,10), and a pilot study using a Bdq-containing regimen to treat a few patients infected with Mycobacterium avium complex (MAC) or Mycobacterium abscessus favored the potential clinical and microbiological activity of Bdq (11). Dlm, a new agent derived from the nitro-dihydro-imidazooxazole class of compounds that inhibits mycolic acid synthesis, has strong in vitro activity against M. tuberculosis, including MDR-TB strains (12)(13)(14).…”

In Vitro Activity of PBTZ169 against Multiple Mycobacterium Species

“…Diseases due to nontuberculous mycobacteria are similar to those due to MDR-TB in that there are few treatment options available, especially for patients with M. avium complex and M. abscessus (24). More importantly, relatively less effort has been devoted to new drug discovery and development.…”