Iation identified by the algorithm, a thorough literature review was performed, with the objective of

Iation identified by the algorithm, a thorough literature review was performed, with the objective of finding known, and validated, associations to antibiotic resistance. For M. tuberculosis, the isoniazid resistance model contains a single rule which targets the katG gene. This gene encodes the catalase-peroxidase enzyme (KatG), which is responsible for activating isoniazid, a prodrug, into its toxic form. As illustrated in Fig. 3, the k-mers associated with this rule and its equivalent rules all overlap a concise locus of katG, suggesting the occurrence of a point mutation. This locus contains codon 315 of KatG, where mutations S315I, S315G, S315N and S315T are all known to result in resistance [36, 37]. A multiple sequence alignment revealed that these variants were all present in the dataset. The SCM therefore selected a rule thatDrouin et al. BMC Genomics (2016) 17:Page 7 ofFig. 2 Antibiotic resistance models: Six antibiotic resistance models, which are all disjunctions (logical-OR). The rounded rectangles correspond to antibiotics. The circular nodes correspond to k-mer rules. A single border indicates a presence rule and a double border indicates an absence rule. The numbers in the circles show to the number of equivalent rules. A rule is connected to an antibiotic if it was included in its model. The weight of the edges gives the importance of each rule as defined by Eqs. (3) and (4). The models for all 17 datasets are illustrated in Additional file 4: Figure Scaptures the absence of the wild-type sequence at this locus, effectively including the presence of all the observed variants. The MLN9708 manufacturer rifampicin resistance model contains two rules, which target the rifampicin resistance-determining region (RRDR) of the rpoB gene. This gene, which encodes the subunit of the RNA polymerase, is the target of rifampicin. The antibiotic binds to RpoB, which inhibits the elongation of messenger RNA. Mutations in the RRDR PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27488460 are known to cause conformational changes that result in poor binding of the drug and cause resistance [37]. Furthermore, one of the rules has a much greater importance than the other. This suggests the existence of two clusters of rifampicin resistant strains, one being predominant,while both harbor mutations in different regions of the RRDR. For S. pneumoniae, the first and most important rule of the erythromycin resistance model targets the mel gene. The mel gene is part of the macrolide efflux genetic assembly (MEGA) and is known to confer resistance to erythromycin [38, 39]. Of note, this gene is found on an operon with either the mefA or the mefE gene, which are also part of the MEGA and associated with erythromycin resistance [38]. It is likely that the algorithm targeted the mel gene to obtain a concise model that includes all of these resistance determinants. The second rule in the model is an absence rule that targets the wild-type version of the metE gene. This gene is involved in the synthesisFig. 3 Going beyond k-mers: This figure shows the location, on the katG gene, of each k-mer targeted by the isoniazid model (rule and equivalent rules). All the k-mers overlap a concise locus, suggesting that it contains a point mutation that is associated with the phenotype. A multiple sequence alignment revealed a high level of polymorphism at codon 315 (shown in red). The wild-type sequence (WT), as well as the resistance conferring variants S315G, S315I, S315N and S315T, were observed. The rule in the model captures the absenc.