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
developed
a 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