Oldfield's Multitarget TB Drug Could Have Other Uses

Date

04/01/14

A drug under clinical trials to treat tuberculosis could be the basis for a class of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study by University of Illinois chemists and collaborators.

Led by U. of I. chemistry professor Eric Oldfield, the team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug can be tweaked to target other pathogens from yeast to malaria – and how targeting multiple pathways reduces the probability of pathogens becoming resistant. SQ109 is made by Sequella Inc., a pharmaceutical company.

“Drug resistance is a major public health threat,” Oldfield said. “We have to make new antibiotics, and we have to find ways to get around the resistance problem. And one way to do that is with multitarget drugs. Resistance in many cases arises because there’s a specific mutation in the target protein so the drug will no longer bind. Thus, one possible route to attacking the drug resistance problem will be to devise drugs that don’t have just one target, but two or three targets.”

Oldfield read published reports about SQ109 and realized that the drug would likely be multifunctional because it had chemical features similar to those found in other systems he had investigated. The original developers had identified one key action against tuberculosis – blocking a protein involved in building the cell wall of the bacterium – but conceded that the drug could have other actions within the cell as well since it was found to kill other bacteria and fungi that lacked the target protein. Oldfield believed he could identify those actions – and perhaps improve upon SQ109.

“I was reading Science magazine one day and saw this molecule, SQ109, and I thought, that looks a bit like molecules we’ve been studying that have multiple targets,” Oldfield said. “Given its chemical structure, we thought that some of the enzymes that we study as cancer and antiparasitic drug targets also could be SQ109 targets. We hoped that we could make some analogs that would be more potent against tuberculosis, and maybe even against parasites.”

By studying SQ109 for themselves, Oldfield’s team determined that SQ109 does indeed block other proteins involved in critical functions in bacteria, fungi and parasites – but not humans. They found it inhibits two enzymes that make the molecule menaquinone, which is involved in generating the cell’s energy. Then they found that SQ109 had a third action, called uncoupling, which makes the cell membrane permeable – essentially transforming the membrane from a wall to a screen door.

Then, the team created a dozen chemical analogs – molecules that are structurally and functionally similar, but tweaked to be more effective or less toxic – and tested them against cultures of bacteria, fungi, parasites and human cells. They found that they could make analogs with maximum effectiveness against certain classes of pathogens; for example, one analog turned out to be five times more potent against the tuberculosis bacterium than the original SQ109. They also found analogs that kill the parasites that cause the most serious and common form of malaria.

Now, the researchers are working with international collaborators to apply SQ109 analogs against other infectious diseases rampant in the tropical world, such as Chagas’ disease, leishmaniasis and sleeping sickness.

Oldfield believes that multiple-target drugs, like SQ109 and its analogs, hold the key to antibiotic development in the age of drug resistance and the rise of so-called “superbugs.” Evidence supports that assessment: So far, in experiments with tuberculosis, no instances of SQ109 resistance have been reported.

The National Institutes of Health supported this work.

Originally Printed on UIUC News Bureau Website (original link)
by: Liz Ahlberg

Custom Tags

Related People

Directory

scheelinAlexander
Scheeline
bjmccallBenjamin
McCall
cmartn10Calgary
Martin
r-gennisRobert
Gennis
j-gerltJohn
Gerlt
sgranickSteve
Granick
mgruebelMartin
Gruebele
hergenroPaul
Hergenrother
huangRaven
Huang
mlkraftMary
Kraft
leckbandDeborah
Leckband
yi-luYi
Lu
martinisSusan
Martinis
snairSatish
Nair
eoldfielEric
Oldfield
rienstraChad
Rienstra
cmsCharles
Schroeder
zanZaida
Luthey-Schulten
sksScott
Silverman
s-sligarStephen
Sligar
zhao5Huimin
Zhao
mselfba2Michelle
Self-Ballard
pbraunPaul
Braun
mdburkeMartin
Burke
jeffchanJefferson
Chan
sdenmarkScott
Denmark
dlottDana
Dlott
foutAlison
Fout
agewirthAndrew
Gewirth
ggirolamGregory
Girolami
shs3Sharon
Hammes-Schiffer
sohirataSo
Hirata
kamihullKami
Hull
jainPrashant
Jain
jkatzeneJohn
Katzenellenbogen
nmakriNancy
Makri
douglasmDouglas
Mitchell
jsmooreJeffrey
Moore
murphycjCatherine
Murphy
r-nuzzoRalph
Nuzzo
dimerPhilip
Phillips
rauchfuzThomas
Rauchfuss
joaquinrJoaquín
Rodríguez-López
jrogersJohn
Rogers
sarlahDavid
Sarlah
kschweizKenneth
Schweizer
jsweedleJonathan
Sweedler
vddonkWilfred
van der Donk
renskeRenske
van der Veen
vuraweisJosh
Vura-Weis
mcwhite7M.
White
sczimmerSteven
Zimmerman
beakPeter
Beak
wklemperWalter
Klemperer
jdmcdonaJ.
McDonald
mvp11Michael
Pak
pogoreloTaras
Pogorelov
mshen233Mei
Shen
dewoonDavid
Woon
wboulangWilliam
Boulanger
rxbRohit
Bhargava
qchen20Qian
Chen
jianjuncJianjun
Cheng
hy66Hong
Yang
andinomaJosé
Andino Martinez
decosteDonald
DeCoste
thhuangTina
Huang
tjhummelThomas
Hummel
dkellDavid
Kell
doctorkMichael
Koerner
marvilleKelly
Marville
crrayChristian
Ray
tlbrownTheodore
Brown
rmcoatesRobert
Coates
thdjrThom
Dunning,
dykstraClifford
Dykstra
j-jonasJiri
Jonas
j-lisyJames
Lisy
shapleyJohn
Shapley
pshapleyPatricia
Shapley
awieckowAndrzej
Wieckowski
zumdahl2Steven
Zumdahl
ksuslickKenneth
Suslick
jlbearJodi
Bear
jcoxJenny
Cox
ealthausEllen
Althaus
staciryStaci
Ryan
sqdSean
Drummond
dmillsDouglas
Mills
sheeleySarah
Sheeley
jsmaddenJoseph
Madden
cknight4Connie
Knight
schulzeHeather
Schulze
slangleySamantha
Langley
ssmurrayStar
Murray
kbaumgarKeena
Finney
adkssnBeatrice
Adkisson
bmylerBeth
Myler
trabari1Katie
Trabaris
kewatsonKaren
Watson
strussTheresa
Struss
metclfKara
Metcalf
ljohnso2Lori
Johnson
jlwJamison
Lowe
jenruslJennifer
Russell
lchenoweLeslie
Chenoweth
jcfJonathan
Freiman
wdedoWolali
Dedo
ebielserElaina
Kutz
spinnerDavid
Spinner
plblumPatricia
Simpson
stevens2Chad
Stevens
lsagekarLori
Sage-Karlson
bertholdDeborah
Berthold
kecarlsoKathryn
Carlson
tlchen4Timothy
Chen
sdesmondSerenity
Desmond
angelaecAngela
Crawford
hsahmed3Hajira
Ahmed
kakinsKenye
Akins
asali3Arzeena
Ali
axelson2Jordan
Axelson
bai11Yugang
Bai
scbakerStephanie
Baker
duffin2Kevin
Duffin
duttadDebapriya
Dutta
pflotschPriscila
Falagan Lotsch
iflemingIan
Fleming
dgrayDanielle
Gray
thennes2Thomas
Hennessey
mhettingMary Jo
Hettinger
holdaNancy
Holda
holler2Jordan
Holler
aibarrAlejandro
Ibarra
kimshSung Hoon
Kim
kocherg2Nikolai
Kocherginsky
philipk2Philip
Kocheril
dlee106David
Lee
legare2Stephanie
Legare
alewandoAgnieszka
Lewandowska
qianliliQianli
Li
bdmccallBirgit
McCall
smccombiStuart
McCombie
jdm5Justin
McGlauchlen
egmooreEdwin
Moore
myerscouKathleen
Myerscough
snalla2Siva
Nalla
oraham2Aaron
Oraham
lah5LeeAnn
Pannebaker
poonawa2Maria
Poonawalla
rrollerR.
Roller
romanovaElena
Romanova
roubakhiStanislav
Rubakhin
vsfVictoria
Shepherd-Fortner
shvedalxAlexander
Shved
asoudaAlexander
Soudakov
ktsween2Kalee
Sweeney
sktarterSamantha
Tarter
aathoma2Andy
Thomas
kwilhelKaren
Wilhelmsen
wilkeyRandy
Wilkey
luxu3Lu
Xu
yuanyao4Yuan
Yao
silongSilong
Zhang
schlembaMary
Schlembach
emccarr2Elise
McCarren
cmercierChristen
Mercier
atimpermAaron
Timperman
niesShuming
Nie
hshanHee-Sun
Han
mmgMutha
Gunasekera