Systems-level analysis of NalD mutation, a recurrent driver of rapid drug resistance in acute Pseudomonas aeruginosa infection
Fig 8
Evolved metabolic-level adaptations in the aztreonam-resistant strain.
(A) Metabolic flux changes relative to the reference condition S0 (D-3rsw, no aztreonam). (B) Venn diagram showing the overlap between reactions whose flux levels significantly altered by aztreonam alone, mutations alone, and their combination. Among all 48 reactions constitutively modulated by mutations (i.e., constitutive mutation effects), 30 are directly related to aztreonam resistance (because aztreonam can induce their responses) and 18 are indirectly related. (C) Grouping of the 48 constitutively modulated reactions by pathways they belong to. (D) Expression of eda serves as a bottleneck to the flux through the Entner-Doudoroff (ED) pathway (red arrows). The connected Embden-Meyerhof-Parnas (EMP) pathway (green arrows) and pentose phosphate (PP) pathway (blue arrows), as well as the relative expression changes of the major genes in the three pathways (heatmap) are also shown. Tpi: triose phosphate isomerase; fba: fructose-1,6-biphosphate aldolase; fbp: fructose-1,6-biphosphatase; pgi: glucose-6-phosphaate isomerase; zwf: glucose-6-phosphate dehydrogenase; pgl: 6-phosphogluconolactonase; edd: phosphogluconate dehydratase; eda: 2-dehydro-3-deoxy-phosphogluconate aldolase; DHAP: dihydroxyacetone phosphate: FDP: D-fructose-1,6-biphosphate; F6P: fructose-6-phosphate; G6P: glucose-6-phosphate; PGL: 6-phospho-D-glucono-1,5-lactone; 6PG: 6-phospho-D-gluconate; KPDG: 2-dehydro-3-deoxy-6-phospho-D-gluconate; G3P: glyceraldehyde 3-phosphate; PYR: pyruvate.