The biologically active congeners (oligomers) of indole-3-carbinol, a dietary component found exclusively in cruciferous vegetables, have been shown to have broad-spectrum antibacterial activities against Gram-positive and Gram-negative bacteria. Using computer-aided drug discovery approach we superimposed their low-energy conformers of the four chemically distinct active oligomers (DIM, LT, CT, and ICZ), and have identified a common structural feature that may be responsible for their antimicrobial activity. We synthesized derivatives around this lead scaffold and correlated the biologic activity of these agents to establish SAR models. We conducted SAR-guided structure modifications and have successfully developed a novel class of orally active, effective, and well-tolerated bactericidal agents. Our lead compound has demonstrated in vitro bactericidal activity against several multidrug-resistant pathogens and agents of bioterrorism, such as F. tularensis, Bacillus anthracis, and Brucella abortus. Mechanistic studies strongly suggest that this novel class of antibiotics is distinct from known classes of antibiotics, such as vancomycin, rifampicin, quinolones, and tetracyclines. Time-kill studies indicate our lead has faster bactericidal activity than ciprofloxacin or gentamicin against both ciprofloxacin-susceptible and ciprofloxacin-resistant SCHU S4. It has almost equal activity against methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), community-associated MRSA (CA-MRSA), and hospital-acquired MRSA (HA-MRSA), as well as vancomycin-intermediate S. aureus (VISA). This novel class of atibiotics appears to have a unique mode of action by inhibiting the macromolecular synthesis of DNA, RNA, and protein, and it has a high genetic barrier to resistance. Preliminary toxicity study indicated our novel antibiotic has a good safety profile.

Computer-aided rational drug design: Develop novel antibiotics to treat drug-resistant bacteria

251st National Meeting (2016)

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