Recent studies have shown that intermediate levels of resistance can also affect patient outcomes, however, we do not yet know the range of mutations that can cause intermediate resistance.

The bacterial mutations that cause high-level drug resistance have largely been identified allowing for the development of rapid diagnostics. In response to widespread use of antibiotics, Mtb has evolved resistance mutations that increase the amount of antibiotic required to inhibit its growth and undermine effective treatment. Tuberculosis disease is treated with a combination of antibiotics targeting the bacterial pathogen Mycobacterium tuberculosis (Mtb). Discovering genetic mechanisms that reduce drug susceptibility and support the evolution of high-level drug resistance will guide development of biomarkers capable of prospectively identifying patients at risk of treatment failure in the clinic. tuberculosis have evolved mutations in a previously uncharacterized DnaA pathway that quantitatively increases resistance to the key first-line antibiotic isoniazid. Reconstructing clinically prevalent mutations in this DnaA interaction site reproduces the phenotypes of dnaA mutants, suggesting that clinical strains of M. To identify DnaA interactors relevant to this phenotype, we perform the first genome-wide biochemical mapping of DnaA binding sites in mycobacteria which reveals a DnaA interaction site that is the target of recurrent mutation in clinical strains. tuberculosis survival during isoniazid treatment via reduced expression of katG, the activator of isoniazid. We demonstrate that these dnaA mutations specifically enhance M. Through a genome wide association study, we show that non-synonymous mutations in dnaA, which encodes an essential and highly conserved regulator of DNA replication, are associated with drug resistance in clinical M. Clinical strains of Mycobacterium tuberculosis exhibit extensive quantitative variation in antibiotic susceptibility but the genetic basis behind this spectrum of drug susceptibility remains ill-defined.

However, reduced susceptibility to antibiotics-even below this breakpoint-is associated with poor treatment outcomes in the clinic, including in tuberculosis.

Genomic dissection of antibiotic resistance in bacterial pathogens has largely focused on genetic changes conferring growth above a single critical concentration of drug.

Claimed by the Orc by Jessica Grayson