Targeting druggable enzymome by exploiting natural medicines: An in silico–in vitro integrated approach to combating multidrug resistance in bacterial infection

Context: Antibiotic resistance is a major clinical and public health problem. Development of new therapeutic approaches to prevent bacterial multidrug resistance during antimicrobial chemotherapy has thus been becoming a primary consideration in the medicinal chemistry community.

Objective: We described a new strategy that combats multidrug resistance by using natural medicines to target the druggable enzymome (i.e., enzymatic proteome) of Staphylococcus aureus.

Materials and methods: A pipeline of integrating in silico analysis and in vitro assay was purposed to identify antibacterial agents from a large library of natural products with diverse structures, high drug-likeness, and relatively low flexibility, with which a systematic interactome of 826 natural product candidates with 125 functionally essential S. aureus enzymes was constructed via a high-throughput cross-docking approach. The obtained docking score matrix was then converted into an array of synthetic scores; each corresponds to a natural product candidate. By systematically examining the docking results, a number of highly promising candidates with potent antibacterial activity were suggested.

Results: Three natural products, i.e., radicicol, jorumycin, and amygdalin, have been determined to possess strong broad-spectrum potency combating both the drug-resistant and drug-sensitive strains (MIC value <10 μg/ml). In addition, some natural products such as tetrandrine, bilobalide, and arbutin exhibited selective inhibition on different strains.

Discussion and conclusion: Combined quantum mechanics/molecular mechanics analysis revealed diverse non-bonded interactions across the complex interfaces of newly identified antibacterial agents with their putative targets GyrB ATPase and tyrosyl-tRNA synthetase.