The novel small molecules, based on new target, new chemical structure and new antimicrobial mechanism, are different from those of existing antibiotics. The new drug candidates demonstrate much effective abilities of inhibiting bacterial growth than commonly used antibiotics, yet with no toxicity to Human Cells.
The development of "Nusbiarylins," a new class of antimicrobial agents, by the research team of the State Key Laboratory of Chemical Biology and Drug Discovery of PolyU's Department of Applied Biology and Chemical Technology (ABCT), is thus a breakthrough in the battle against multi-drug resistant bacterial infections.
The researchers developeda model basing on the structure of NusB and NusE, and applied computer-aided screening to screen about 5,000 small molecule compounds with drug-like properties to explore for inhibitors for NusB-NusE interaction. The shortlisted compounds were then put to tests for antimicrobial activity against different Mrsa Strains. A compound, (E)-2-{[(3-ethynylphenyl)imino]methyl}-4-nitrophenol (hereafter addressed as MC4), was identified as having much effective antibacterial abilities than the commonly used antibiotics. The Minimum Inhibitory Concentration (note: MIC denotes the lowest concentration of a chemical/drug for preventing bacterial growth) of MC4 for some MRSA strains are as low as 8 ?g/mL, compared to the MICs of >64 ?g/mL demonstrated by two antibiotics in the market, oxacillin and gentamicin.
Test of MC4 on Human lung and skin cells (infections caused by MRSA often occur in these tissues) indicated no significant toxicity. The fact that NusB and NusE exist only in bacteria and not human cells has also addressed toxicity concern.
The research team has further structurally modified MC4 for optimization, and 167 analogues were synthesized so far. The new class of compounds are named as "Nusbiarylins" (basing on their target protein "NusB" and their "biaryl" structure). Laboratory test of Nusbiarylins against a panel of MRSA strains proved their consistent antibacterial activity, some with MIC as low as 0.125 ?g/mL, much better than commonly used antibiotics, including vancomycin with the MIC of 1 ?g/mL which is labelled as the "last resort" antibiotic drug in the United States.
Further pre-clinical studies on the in vitro pharmacological properties of Nusbiarylins on human cells indicated that the compounds: leading to nearly no hemolysis (i.e. human blood cell breaking), an indication of being safe for injection; and with excellent result in intestine absorption, implying being effective for oral taking.
See:
Yangyi Qiu, Shu Ting Chan, Lin Lin, et al Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins. Bioorganic Chemistry, 2019; 92: 103203 DOI: 10.1016/j.bioorg.2019.103203
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
