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. 2010 Dec;4(4):311-22.
doi: 10.1007/s11693-011-9076-5. Epub 2011 Feb 20.

Protein-protein interaction networks suggest different targets have different propensities for triggering drug resistance

Jyothi Padiadpu  1 , Rohit Vashisht, Nagasuma Chandra
Affiliations

Protein-protein interaction networks suggest different targets have different propensities for triggering drug resistance

Jyothi Padiadpu et al. Syst Synth Biol. 2010 Dec.

Abstract

Emergence of drug resistance is a major problem in the treatment of many diseases including tuberculosis. To tackle the problem from a wholistic perspective, it is essential to understand the molecular mechanisms by which bacteria acquire drug resistance using a systems approach. Availability of genome-scale data of expression profiles under different drug exposed conditions and protein-protein interactions, makes it feasible to reconstruct and analyze systems-level models. A number of proteins involved in different resistance mechanisms, referred to as the resistome are identified from literature. The interaction of the drug directly with the resistome is unable to explain most resistance processes adequately, including that of increased mutations in the target's binding site. We recently hypothesized that some communication might exist from the drug environment to the resistome to trigger emergence of drug resistance. We report here a network based approach to identify most plausible paths of such communication in Mycobacterium tuberculosis. Networks capturing both structural and functional linkages among various proteins were weighted based on gene expression profiles upon exposure to specific drugs and betweenness centrality of the interactions. Our analysis suggests that different drug targets and hence different drugs could trigger the resistome to different extents and through different routes. The identified paths correlate well with the mechanisms known through experiment. Some examples of the top ranked hubs in multiple drug specific networks are PolA, FadD1, CydA, a monoxygenase and GltS, which could serve as co-targets, that could be inhibited in order to retard resistance related communication in the cell.

Keywords: Emergence of resistance; Network analysis; Resistome.

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Figures

Fig. 1
Fig. 1
Flow chart shows here the methodology followed to derive individual target to resistance paths network, form curation of the drug targets for each drug in the TB regimen and proteins involved in the resistance machineries known, building interactome network of shortest paths with incorporation of the specific drug exposed microarray data to score and finally to rank the paths
Fig. 2
Fig. 2
Drug specific networks (a) Isoniazid; all possible targets of isoniazid as source (see Table 1), inset- InhA alone as the source (b) Ofloxacin, (C) Ethambutol, (d) Rifampicin (e) Streptomycin and (f) Amikacin. Nodes represent the proteins while the edges indicate interactions between them. Fold-changes in gene expression upon drug exposure, from genome scale microarray data, are incorporated as weights to the network and are indicated in the figure through node colours: (green-down-regulated, yellow- no fold-change, red- up-regulated and grey- not expressed or not studied in the data considered). The size of the node is proportional to the expression level. Different classes of the resistance proteins are shown in different shapes: SOS (hexagonal), Pumps (parallelogram), HGT (triangle), Cytochromes (rounded-rectangle) and drug targets are shown as arrow heads. The edge thickness is proportional to the edge weight
Fig. 3
Fig. 3
Distribution of path scores (a) for the set of target for each drug shown, when all resistance mechanisms are considered and (b) for the SOS mechanism alone. The X- axis shows the individual drug and Y- axis represents the path score. Red bars in both (a) and (b) correspond to top ranks (or least path scores) while blue bars in (a) correspond to scores for an average of the top hundred ranks
Fig. 4
Fig. 4
Number of top ranking unique resistance paths in different score ranges (as indicated in the colour key), for different drugs to different resistance classes
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