title: Targeting druggable enzymome by exploiting natural medicines: An in silico-in vitro integrated approach to combating multidrug resistance in bacterial infection.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Department of Public Health Management , The Affiliated Hospital of Weifang Medical University , Weifang , China .
authors.forename: Ping
authors.initials: P
authors.lastname: Zang
authors.affiliation: b Department of Central Sterile Supply , Changyi People's Hospital , Changyi , China .
authors.forename: Aijie
authors.initials: A
authors.lastname: Gong
authors.affiliation: c Department of Medical , and.
authors.forename: Peirong
authors.initials: P
authors.lastname: Zhang
authors.affiliation: d Department of Gynaecology , The Affiliated Hospital of Weifang Medical University , Weifang , China.
authors.forename: Jinling
authors.initials: J
authors.lastname: Yu
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D001688:Biological Products / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D016503:Drug Delivery Systems / Q000379:methods*; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests / Q000379:methods; D062105:Molecular Docking Simulation / Q000379:methods; D017433:Protein Structure, Secondary; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000201:enzymology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology
chemical_list: D000900:Anti-Bacterial Agents; D001688:Biological Products; D007527:Isoenzymes
keywords: Antibiotic resistance; molecular docking; rational drug design; virtual screening