Abstract
The emergence of superbugs that are resistant to last-resort antibiotics poses a serious threat to human health, and we are in a “race against time to develop new antibiotics.” New approaches are urgently needed to control drug-resistant pathogens, and to reduce the emergence of new drug-resistant microbes. Targeting bacterial virulence has emerged as an important strategy for combating drug-resistant pathogens. It has been shown that pyocyanin, which is produced by the phenazine biosynthesis pathway, plays a key role in the virulence of Pseudomonas aeruginosa infection, making it an attractive target for anti-infective drug discovery. In order to discover efficient therapeutics that inhibit the phenazine biosynthesis in a timely fashion, we screen 2004 clinical and pre-clinical drugs to target multiple enzymes in the phenazine biosynthesis pathway, using a novel procedure of protein–ligand docking. Our detailed analysis suggests that kinase inhibitors, notably Lifirafenib, are promising lead compounds for inhibiting aroQ, phzG, and phzS enzymes that are involved in the phenazine biosynthesis, and merit further experimental validations. In principle, inhibiting multiple targets in a pathway will be more effective and have less chance of the emergence of drug resistance than targeting a single protein. Our multi-target structure-based drug design strategy can be applied to other pathways, as well as provide a systematic approach to polypharmacological drug repositioning.
Highlights
The emergence of multi-drug resistance and extensively drug-resistant microbes to antibiotics poses a great threat to human health [1]
The effectiveness of P. aeruginosa as a pathogen can be attributed to its arsenal of virulence mechanisms and its large metabolic capacity, including its ability to intrinsically resist antibiotics owing to its impermeable outer membrane, efflux capabilities, tendency to colonize surfaces in a biofilm form, and ability to acquire and maintain antibiotic plasmids [5]
The treatment of P. aeruginosa wild-type strains PA01 and PA14 with raloxifene resulted in a dose-dependent reduction in pyocyanin production in vitro. These results suggest that targeting the phenazine biosynthesis pathway may be suitable for further development as a therapeutic method for treating P. aeruginosa infections, and such already-approved drugs may be computationally screened and potentially repurposed as novel anti-virulence agents
Summary
The emergence of multi-drug resistance and extensively drug-resistant microbes to antibiotics poses a great threat to human health [1]. New approaches are needed to control drug-resistant pathogens and reduce the emergence of multi-drug-resistant microbes, which are costly to treat and can lead to serious treatment failures [3]. Targeting virulence factors and pathogen–host interactions has emerged as a promising strategy in antibacterial drug discovery [4]. Such an approach places less selective pressure on bacteria to evolve new strategies for survival, and is more specific to pathogens and subject to less selection for drug resistance. Novel approaches for the treatment of P. aeruginosa infection are urgently needed
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