High throughput crystallography of TB drug targets.
Tuberculosis (TB) infects one-third of the world population. Despite 50 years of available drug treatments, TB continues to increase at a significant rate. The failure to control TB stems in part from the expense of delivering treatment to infected individuals and from complex treatment regimens. Incomplete treatment has fueled the emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Reducing non-compliance by reducing the duration of chemotherapy will have a great impact on TB control. The development of new drugs that either kill persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multidisciplinary approach that will identify and characterize new drug targets that are essential for persistent Mtb. Targets are exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Our core structural genomics pipeline works with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analysis will be completed by the individual laboratories. We also have capabilities for functional analysis and the virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository for TB research reagents, and discover chemical inhibitors of drug targets for future development of lead compounds.
Murillo
A C
AC
Texas A&M University, Department of Biochemistry and Biophysics, College Station 77843-2128, USA.
Li
H Y
HY
Alber
T
T
Baker
E N
EN
Berger
J M
JM
Cherney
L T
LT
Cherney
M M
MM
Cho
Yoon Song
YS
Eisenberg
D
D
Garen
C R
CR
Goulding
C W
CW
Hung
L W
LW
Ioerger
T R
TR
Jacobs
W R
WR
James
M N G
MN
Kim
C
C
Krieger
I
I
Lott
J S
JS
Sankaranarayanan
R
R
Segelke
B W
BW
Terwilliger
T C
TC
Wang
F
F
Wang
S
S
Sacchettini
J C
JC
D000995:Antitubercular Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D003461:Crystallography; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007501:Iron / Q000378:metabolism; D008292:Malate Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry; D046210:Microfluidic Analytical Techniques; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009171:Mycolic Acids / Q000037:antagonists & inhibitors; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry; D014961:X-Ray Diffraction
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C106638:HisG protein, bacteria; D009004:Monosaccharide Transport Proteins; D009171:Mycolic Acids; D001120:Arginine; D007501:Iron; D008292:Malate Synthase; D010453:Peptide Synthases; C022318:pantothenate synthetase