Table 2. A core set of genes and pathways are predictive of drug interactions
GeneGene nameRankAssociated withP‐value (t‐test)
Sensitive in
One drugBoth drugs
(A)
glmSl‐Glutamine: d‐fructose‐6‐phosphate aminotransferase1Synergy0.1310−6
mdtKMultidrug efflux protein2Synergy10−30.17
greATranscription elongation factor3Antagonism10−710−5
asmAPutative assembly protein4Synergy10−510−5
prpCMethylcitrate synthase5Antagonism10−110.31
yfiNPredicted diguanylate cyclase6Antagonism10−110.31
cyaYFrataxin, iron‐binding and oxidizing protein7Synergy0.050.01
cspECold shock protein8Antagonism10−100.09
rfbXPredicted polisoprenol‐linked O‐antigen transporter9Antagonism10−510−3
yphFPutative LACI‐type transcriptional regulator10Synergy0.120.05
PathwayP‐valueFDRAssociated withSimilar or dissimilar between drugs
(B)
Homologous recombination10−50.02AntagonismDissimilar
Ribosome10−40.02
Purine metabolism10−40.02Synergy
Mismatch repair10−40.04AntagonismDissimilar
Lipopolysaccharide biosynthesis10−40.04SynergySimilar
Drug resistance10−40.04SynergySimilar
Pentose phosphate pathway10−30.04
Alanine, aspartate, and glutamate metabolism10−30.04Synergy and Antagonism
Pyrimidine metabolism10−30.09Synergy
Bacterial chemotaxis10−30.09
Bacterial secretion system10−30.09
Peptidoglycan biosynthesis0.020.19
Oxidative phosphorylation0.030.22Synergy and AntagonismDissimilar
  • (A) Top 10 genes most predictive of antibiotic interactions inferred by INDIGO and their correlation with synergy or antagonism across all drug interactions are shown. Further, the presence of these genes in either one (dissimilar) or both (similar) the antibiotics’ chemogenomic profile led to different effects on the interaction outcome. For example, the top predictor gene, glmS, is significantly associated with synergy when present in the profile of both the drugs (P‐value = 10−6), but not when present in only one of the drugs in a drug pair (P‐value = 0.13). (B) Top 10 KEGG pathways enriched among the top 250 DIR genes. The enrichment of these pathways among genes that were either significantly (P‐value < 0.05; FDR < 0.25) associated with synergy or antagonism is displayed in columns 2 and 3. For example, the homologous recombination pathway was significantly enriched among the top 250 genes (P‐value = 10−5). In addition, this pathway was significantly enriched among genes that were strongly associated with antagonism (P‐value < 0.05) when present in one of the drugs in a drug pair (dissimilar). Empty boxes indicate no significant enrichment toward synergy or antagonism.