Clinically prevalent mutations in Mycobacterium tuberculosis alter propionate metabolism and mediate multidrug tolerance

Abstract

The global epidemic of drug-resistant tuberculosis is a catastrophic example of how antimicrobial resistance is undermining the public health gains made possible by combination drug therapy. Recent evidence points to unappreciated bacterial factors that accelerate the emergence of drug resistance. In a genome-wide association study of Mycobacterium tuberculosis isolates from China, we find mutations in the gene encoding the transcription factor prpR enriched in drug-resistant strains. prpR mutations confer conditional drug tolerance to three of the most effective classes of antibiotics by altering propionyl-CoA metabolism. prpR-mediated drug tolerance is carbon-source dependent, and while readily detectable during infection of human macrophages, is not captured by standard susceptibility testing. These data define a previously unrecognized and clinically prevalent class of M. tuberculosis variants that undermine antibiotic efficacy and drive drug resistance.

In-host population dynamics ofM. tuberculosisduring treatment failure

“…5D). Single in-host SNPs occurred in 275 eight additional known resistance loci including three intergenic regions, and in prpR, a gene 276 recently implicated with drug tolerance (Hicks et al 2018) (Table S8). 277…”

Glutamine metabolism modulates azole susceptibility inTrypanosoma cruziamastigotes

“…Even within a single tissue, the presence of an inflammatory response shifts the local metabolism (Kominsky et al, 2010) and in many cases leads to intracellular nutrient restriction to control pathogen growth (Grohmann et al, 2017). Pathogen growth in vitro cannot always reflect the complete spectrum of metabolic environments present in vivo and consequently can confound interpretations of standard antimicrobial assays (Hicks et al, 2018; Pethe et al, 2010). These considerations are especially pertinent with regard to T. cruzi , a parasite that in its mammalian host replicates intracellularly in diverse tissues and persists for the lifetime of the host, exposing the parasite to an immune response that suppresses parasitemia without sterile cure (Lewis et al, 2015).…”

“…Recent work has shown that when the metabolic state and growth rate of microbes are disentangled, the factor that correlates with antibiotic efficacy is the microbial metabolic state (Lopatkin et al, 2019). Similarly, standard in vitro inhibitory activity of a candidate compound can be confounded by altered pathogen metabolism due to growth media composition (Hicks et al, 2018; Pethe et al, 2010) and conversely an understanding of these interactions can potentiate treatment (Vestergaard et al, 2017). These complex interactions are best understood in cases of bacterial pathogenesis, but recently, similar trends are apparent in eukaryotic pathogens (Dumont et al, 2019; McLean and Jacobs-Lorena, 2017; Murithi et al, 2020).…”

Model-based integration of genomics and metabolomics reveals SNP functionality in Mycobacterium tuberculosis

“…MTBC strains cluster into seven distinct phylogeographic lineages 2 that have been proposed to be adapted to different host populations 51 . Current GWAS methods for relating genetic variation to phenotype, were successful in identifying clinically prevalent mutations that confer strong phenotypes such as drug resistance 31 . However, because the genetic diversity in MTBC strains is small compared to other pathogens 52,6 , such standard methods struggle to relate genetic variation to host adaptation.…”

“…Moreover, we do not know of any validation of these methods in microbes. As a result, only a small proportion of SNPs in the MTBC have been mechanistically linked to phenotypes such as virulence or intrinsic drug resistance 31,32 .…”