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proteins, with all known Gene Ontology molecular process networks. This analysis resulted in 558 overlapping and cause-effect constraint sub-net- works of varying sizes and topologies. These frag- ments were then used in high volume data transfor- mation to identify information densities (network reachability information)of >22,000 drugs, natural products, herbs, bacteria and antibiotics (stimuli). Hierarchical clustering of this network reacha-
bility information identified stimuli-induced routes of information transfer between the 558 sub-net- works and groups of substances inducing similar cross-linking patterns of the 558 molecular pro- cesses (sub-networks). Phenotypes containing 17 drug-resistant strains listed by the WHO are shown in Figure 5. The cross-linking of 558 molecular processes
involves modification of protein-protein interac- tions. Consequently, substances grouped in specific phenotypes modulate similar protein-protein inter- actions. As shown in Figure 6, stimuli residing in well-defined phenotypes, such as Phenotype A, modulate similar protein-protein interactions and are hence anticipated to interact with each other. Examples of molecular processes modulated by substances in Phenotype A include chemotaxis, DNA replication, regulation of cell death, etc. The network prediction of whether stimuli (bac-
teria, herbs, drugs) in Phenotype A are indeed capable of targeting bacteria was validated by review of published articles. A summary of these
Drug Discovery World Summer 2018
findings is listed in Table 1. As shown, 10 out of 15 substances in phenotype A have direct antibacterial activities, five have been shown to modify bacterial resistance and one of these, 5-androstenediol has been shown to modify bacterial virulence. Of significance for drug repositioning is the
interaction of polidocanol with antibiotics. Polidocanol has been shown to reduce the mini- mum inhibitory concentration (MIC) of methi- cillin, oxacillin, penicillin G and ampicillin against drug-resistant Staphylococci. The authors suggest that the inhibition by polidocanol involves more general resistance mechanisms since it was not inhibitory as a single agent for Staphylococci and did not inhibit beta-lactamase activity32. EBA-based identification of herbs sharing
Phenotype A characteristics suggests that these plants are prime candidates for bioprospecting and discovery of potentially novel anti-bacterial agents to overcome multi-drug resistance. Experimental validation of EBA findings for
seeking drug repositioning candidates was pursued by us via in vitro studies to measure increased sus- ceptibility of E. coli, S. aureus and MRSA strains to known antibiotics in presence of compounds identified by EBA screening. Our preliminary find- ings (data not shown) indicate that in situ screen- ing by EBA has identified several marketed drugs that can be readily positioned as modulators of bacterial multi-drug resistance. Efforts are ongoing to confirm these findings in vivo.
49
Figure 5 Clustering of network reachability information: Identification of groups of substances containing 17 drug resistant bacterial strains
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