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From YouTube: Open Source Antibiotics Science Update Jan 22 2021
Description
Weekly open project meeting for Open Source Antibiotics Series 2.
Full Project: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles
Relevant GitHub Issue: https://github.com/opensourceantibiotics/Series-2-Diarylimidazoles/issues/52
On the call: Professor Matthew Todd, Dr Dana Klug, Giada Sabatino (UCL), Dr Chris Swain (Cambridge MedChem Consulting), Anthony Sama (citizen contributor), Lori Ferrins (Northeastern University), Lee Graves (University of North Carolina Chapel Hill)
A
Just
very
briefly,
because
I
ought
to
mention
it
so
we
just
in
the
last
couple
of
weeks,
we've
spoken
about
a
bunch
of
different
molecules
that
may
be
of
interest
for
the
next
round
of
synthesis
and
evaluation,
and
we,
we
discussed
those.
You
know
with
words
and
I'd
written
some
notes
and
dana's
very
kindly
put
those
into
a
diagram
so
that
we
can
just
refer
back
to
this
as
being
these
being
the
current
synthetic
targets,
and
I
think
it
it
encompasses
everything
we
left.
He
goes
and.
B
A
A
So,
hopefully
that's
clear,
and
I
don't
really
want
to
discuss
that
anymore,
because
we've
discussed
it
quite
a
bit
and
there's
some
really
good
targets
there
that
I
think,
are
very
achievable.
So
I
think
that,
in
terms
of
chemistry,
planning
we're
in
good
shape
and
really
the
highest
priority
item
is,
is
the
moa
stuff.
A
So
we
obviously
you
know,
received
the
data
from
lee
and
dana's
put
up
this
explanation
of
what
that
is,
as
well
as
some
the
sort
of
highlight
targets
from
the
sheet
there
and
then
giada
put
up
some
links
for
the
relevant
proteins,
but
that's
kind
of
as
far
as
we've
gotten
here
and
what
I
was
hoping
lee
is.
You
could
enlighten
us
on
on
both
things,
both
things,
the
meaning
of
the
data
and
what
should
be
taken
away
and
then
what
we
ought
to
be
doing
next.
C
Oh
yeah,
I'm
gonna
try
to
remember
exactly
what
was
done
because
it's
been
a
little
while
now
and
my
technician
that
actually
did
the
work
is
in
another
meeting
right
now,
so
he
couldn't
join
us
today.
But
the
idea
was
the
inhibitor
bead
cocktail.
We
have
is
a
broad,
broadly
effective
agent
at
capturing
kinases
and
mass.
C
This
is
the
first
time
we've
ever
applied
it
to
a
microbial
system,
but
the
idea
is
that
these
these
compounds
bind
to
promiscuously
to
the
atp
binding
site,
and
so
we
can
capture
a
large
number,
usually
300
or
so
kinase
and
then
using
quantitative
mass
spectrometry.
We
can
look
at
profiles
of
kinema
differences.
C
What
we
found
to
be
quite
effective
is
looking
at
competition
assays
using
this
platform
as
a
competition
assay
to
look
for
drugs
that
compete
off
kinases
in
a
dose-dependent
manner.
So
basically
the
idea
was,
let's
take
some
staff,
a
cells
and
and
then
incubate
them
with
your
compounds
at
different
concentrations.
C
And
if
I
remember
correctly,
that's
what
we
did,
we
did
both
the
active
and
inactive
compound
that
you
gave
us
and
a
lab
next
door
prepared
the
lysates,
so
we
incubated
the
lysates
with
that
and
then
looked
for
what
things
were
competed
off
in
a
dose-dependent
manner.
So
the
things
we
tend
to
look
for
is
you
know
how
significant,
where
the
peptides
we
get
two
or
more,
where
the
full
change
is
reasonable,
did
it
show
dose
dependency
and
and
then
not
dose
dependency
with
an
inactive
analog?
C
C
C
We
found
that
and
other
people
have
published
this
as
well,
that
oftentimes
kinase
inhibitors
capture,
fats
and
and
other
metabolic
enzymes,
which
you
wouldn't
necessarily
look
at,
but
we
I
asked
my
technician
to
give
you
all
the
data
not
to
filter
it
just
for
kinase.
It's
just
give
you
everything,
so
I'm
anxious
to
see
what
you
guys
actually
have
come
up
with
from
that
list.
C
B
A
So
I
guess
we
had
a
question
last
time
and
please
excuse
any
ridiculously
naive
questions.
We
had
a
question
last
time
of
the
fact
that
if
this
is
the
first
time
you've
applied
it
to
a
microbial
system,
we
were
wondering
about
the
target
list
that
you
came
up
with,
and
you
know
these
are.
Obviously
these
are
inhibitors
of
mammalian
enzymes,
the
listview
centers
of
codes.
These
are
for
we
we
were
confused,
I
guess
about
where
it
crosses
over
from
mammalian
proteins
into
microbial
proteins.
A
C
No,
they
were
what
we
sent
you,
which
is
basically
whatever
the
mass
spec
detected
as
a
significant
change
in
amount
bound
to
the
bead.
So
it
was
all
bacterial
proteins
shouldn't
be
any
other.
Maybe
there
was
occasional
contamination
of
a
keratin
which
happens
sometimes,
but
it
should
have
been
all
bacterial
proteins
in
there,
and
you
know
we
didn't
do
any
kind
of
other
analysis.
Besides
give
you
the
data,
basically.
C
C
Yeah,
no,
that's
a
very
good
question.
You
know
like
I
said
this
is
sort
of
our
first
foray
into
this
organism.
So
they're,
probably
you
know,
we
rely
on
the
libraries,
the
databases
that
are
available
and
bounce
our
data
off,
that
I
think
they're
pretty
good
for
staff.
A
and
that's
you
know:
okay,
it
shouldn't
be
a
lot
of
proteins
that
weren't
identified,
but
I
can
ask
them
that
too.
C
Well,
you
know,
like
I
said,
and
it
would
probably
be
a
bad
idea
for
us
to
do
some
just
unbiased
proteomics,
where
we
treat
the
cells
living
cells
with
the
compounds
for
various
time
points
and
concentrations
and
just
ask:
how
does
the
proteome
respond
to
this
and
we've
done
that
in
other
systems
and
learned
a
lot
about
potential
targets?
You
know
potential
effects
on
metabolism
and
so
on
without
invoking
the
beads
at
all.
I
just
asked
you
know
how
does
the
proteome
respond
to
this,
and
that
could
be
quite
useful
too.
Okay,.
A
Yeah,
I
was
had
a
question
to
do
with
that.
I
mean
my
first
thought
was
that
we
should
look
at
the
the
genes
which
have
been
sorry
the
protein
levels
which
have
been
affected
and
and
asked
if
any
of
them
cluster
and
are
you
know,
related
to
a
particular
pathway
in
the
cell.
But
of
course
I
wouldn't
apply
here,
because
it's
a
lysate,
it
wouldn't
be
right,
whereas
if
you
do
the
experiment
you
just
mentioned,
then
you
might
pick
that
up.
D
C
A
A
C
A
A
E
Right
so
the
the
0.5
or
negative,
0.5
or
plus
0.5,
that
was
from
sort
of
the
powerpoint
that
you,
you
guys
supplied
us
with
lee
to
say
that
this
is
significant.
So
I
looked
at
that
criteria.
I
just
said
at
the
highest
concentration
that
those
criteria
were
met,
and
then
I
looked
for
a
dose
dependency.
E
So
that's
what
I
got
and
I've
I've
gone
through
a
little
bit
of
the
links
that
jada
found.
So
some
of
these
do
have
atp
binding
sites,
so
I
think
that
that
would
kind
of
make
sense.
So
I
guess
my
next
question
is
kind
of.
Is
it
known
that
any
of
these
are
essential
for
bacterial
cell
survival
and
that
I'm
not
sure
about
I'm.
D
Pretty
sure
a
couple
of
them
are
like
extremely
important.
There's
some
germanium
synthase
in
there.
As
you
know,
the
sulfonamides
target
dna
synthesis
and
cause
cell
shut
down
through
there.
As
you
can
see,
there's
a
there's
a
couple
pyridine
and
pyrimidine
synthesis
proteins
such
as
the
pyr,
not
pyr.
D
C
E
C
Right,
yeah,
that's
a
curiosity,
and
we
see
that
with
certain
metabolic
enzymes-
and
I
never
had
a
good
explanation
for
that
now.
There's
two
possibilities:
one
is
that,
through
the
competition
we're
now
pushing
off
some
protein
that
allows
binding
sites
for
one
of
these
other
enzymes
to
preferentially
bind
right,
so
that,
if
you
imagine
that
that
some
because
of
avidity
there's
some
proteins
bind
to
the
beads
and
as
we
compete
them
off
now,
we
provide
binding
sites
for
other
proteins
to
bind.
C
That's
one
possibility.
The
other
is
that
we're
affecting
an
allosteric
site
that
we're
binding
to
an
allosteric
site
and
then
increasing
its
affinity
for
the
bees,
and
we've
seen
this
with
a
lot
of
metabolic
enzymes,
which
makes
me
think
it
might
be
the
latter
that
that
you're
affecting
some
kind
of
allosteric
site
such
that
it
now
prefers
to
bind
to
the
bead
even
tighter.
C
E
C
So
we
we
chose
a
safe
route
which
was
to
make
the
lysate
and
do
the
experiment
that
way,
I
actually
prefer
doing
it
with
live
cells,
because
you
know
you're.
Looking
at
re
competition
with
relevant
atp
concentrations,
you're,
you
haven't
disrupted
some
of
the
scaffolds
and
complexes
that
are
naturally
found
in
the
cell.
That
can
be
the
next
line
of
experimentation,
possibly
to
see
if
we
can
repeat
this
with
live
cells.
Now
dana
when
you
looked
at
the
data,
did
you
say?
Okay,
the
positive
control
compound
gives
this.
C
E
E
E
C
A
D
D
A
A
And
and
zoom
in
on
things
that
are
known
and
then
things
are
unknown
and
then
we're
in
better
shape.
The
one
remaining
question
I
had
about
the
data
also
is
so
the
level
of
activity
that
we've
seen.
It's
not
it's
not
as
if
we're
dealing
with
with
a
relatively
small
amount
of
influence.
Are
we
dealing
with
you
know,
experimental
values
that
are
that
are
typical
or
is
it
near
noise?
You
know
we're
talking
about
significant
impacts
on
some
of
these
relative
experiments.
C
E
C
C
C
C
Yeah
there
were
some
significant
full
changes
with
some
of
them
and
it
may
be
too.
In
some
cases
we
won't
see
such
nice
dose
dependency
it'll,
be
like
a
threshold.
We
hit
a
threshold
and
only
at
the
highest
concentration.
We
see
something
I
probably
should
just
take
a
little
bit
more
time
and
go
through
the
data
too,
and
just
bounce
back
with
dana.
If,
if
I
see
anything
else
that
might
be
important
in
there
yeah.
C
C
Yeah,
let
me
talk
to
my
tech
too.
He
had
told
me
that,
and
I
don't
remember
if
it
was
said
he
wasn't
happy
with
the
amount
of
protein
that
we
didn't
have
quite
as
much
protein
as
we
would
have
liked
to
have
had
for
the
experiment,
so
it
might
be
worth
our
while
to
just
go
ahead
and
repeat
it
with
a
larger
amount
of
protein
and
try
and
get
more
more
proteins
into
the
mix.
That
often
makes
a
difference
in
terms
of
the
results.
A
C
A
A
Like
I
said
lee,
you
know
the
the
three
parts
this
project
are
getting
the
the
potency
better,
and
that
was
all
the
chemical
structures
you
saw
at
the
beginning
is
our
best
guess
of
what
should
change
next
and
then
trying
to
get
rid
of
some
of
the
metabolic
liabilities,
which
is
the
stuff
we're
doing
with
with
monash.
We've
done
a
few
experiments
on
compounds
with
them
and
we're
trying
to
get
a
sort
of
you
know
next
best
compound,
so
that
we
can
send
them
those
towards
the
end
of
the
project.
A
D
A
C
Yeah
well-
and
you
know,
I'm
going
to
say
the
you
know,
the
biggest
danger
with
our
method
is
that
the
protein
that
you're
looking
for
doesn't
bind
to
these
beads
yeah,
and
so
we
don't
ever
see
it,
and
so
we
may
want
to
step
back
and
say:
well,
you
know,
how
can
we
do
an
unbiased,
proteomics
analysis
to
make
sure
we're
not
missing
something
very
important,
yeah
sure?
That's
you
know,
I
don't
want
to.
Let
you
guys
down
yeah.