Identifying co-targets to fight drug resistance based on a random walk model

Abstract

BackgroundDrug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs.ResultsWe use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH)-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes.ConclusionsWith gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

Untargeted Metabolomic Profiling of Amphenicol-Resistant Campylobacter jejuni by Ultra-High-Performance Liquid Chromatography–Mass Spectrometry

“…26,27 Several studies demonstrated that drug resistance in Mycobacterium tuberculosis could decrease gene expression and result in downregulation of glycerophospholipid metabolism, and there was a correlation between cellular drug resistance and alterations in glucosylceramides (belonging to lipids) metabolism in multidrug-resistant cancer cells. 28,29 In this study, we found that the identified glycerophospholipids were overexpressed in both resistant strains. These results suggested that glycerophospholipids exerted an important role in acquiring or maintaining amphenicol resistance in C. jejuni.…”

Global Transcriptional Profiling of Longitudinal Clinical Isolates of Mycobacterium tuberculosis Exhibiting Rapid Accumulation of Drug Resistance

“…Thus from our observations, we infer that even in drug compliant patients, over expression of efflux pumps and under expression of metabolic processes may be responsible for low level resistance to multiple drugs without the presence of multiple drug resistance mutations. Such strains may also exhibit a mutator phenotype [39] due to reduced DNA repair activity observed in the current study. Further exposure of these isolates to anti-TB drugs may cause “ selection and stabilization of spontaneous mutations ”, resulting in clonal expansion of MDR isolates [38], While such mechanisms have been advocated for isoniazid resistance [38], our observations extend these implications to all the first line anti-TB drugs.…”

Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis

“…This confirms that isoniazid susceptibility was not affected by the inactivation of mmr and that the overexpression results observed in the previous studies may be due to a general response to stress rather than a result of isoniazid being a substrate of Mmr. In fact, a recent study that used a computational approach combined with gene expression data and an interactome network has suggested that the SOS response is upregulated under isoniazid treatment (33). This may affect several cellular processes, namely, the regulation of efflux pumps, and be a trigger for drug resistance.…”