Target based discovery of next generation pyrazinamide
Target based discovery of next generation pyrazinamide
批准号:
10404533
负责人:
Thomas Dick
金额:
$79.17万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-08-01 至 2023-05-31
关键词:
Acquired Immunodeficiency SyndromeAffinityAnabolismAnimal ModelAnti-Bacterial AgentsAntibioticsAntitubercular AgentsAntitubercular AntibioticsAspartateAwardBacillusBacteriaBindingBiochemicalBiological AssayBiophysicsCarboxy-LyasesCause of DeathCellsChemistryChimeric ProteinsClinicalDependenceDiseaseDrug KineticsDrug TargetingDrug ToleranceEnzyme InhibitionFrequenciesGenerationsGeneticGoalsGranulomaGrowthHIVHIV SeropositivityHumanImmunityImmunocompetentIn VitroInbred BALB C MiceIndividualInfectionKnowledgeLeadLesionMediatingMedicalMedicineMinorModelingMutationMycobacterium tuberculosisNecrosisNecrotic LesionOryctolagus cuniculusOutcomePatientsPenetrationPeptide HydrolasesPersonsPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacotherapyPlayPopulationPropertyPyrazinamidePyrazinamide resistanceRegimenRelapseReporterResistanceRoleSiteSterilizationTestingTimeTreatment ProtocolsTuberculosisanalogbacterial fitnessbasebiophysical analysisbiophysical techniqueschemotherapycofactorenzyme activityfight againstfitnessgenetic approachimprovedin vitro activityin vivoinhibitorlung lesionmetabolomicsmolecular drug targetmouse modelmutantnext generationnovelprogramsprotein degradationpyrazinoic acidrational designtreatment durationtuberculosis drugs
中文摘要
结核病是艾滋病患者死亡的一个主要原因。在有免疫能力的人群中,药物
英文摘要
Tuberculosis (TB) is a main cause of death for people living with AIDS. In immune-competent populations, drug
therapy and immunity join forces to win the fight against Mycobacterium tuberculosis (Mtb). In HIV-positive
individuals on the other hand, chemotherapy must fully sterilize all infection sites. There is an urgent medical
need to develop more potent `sterilizing' drugs.
The inclusion of pyrazinamide (PZA) into the TB regimen allowed reduction of treatment time to six months, while
maintaining low relapse rates. The pharmacological basis for PZA's remarkable sterilizing activity in patients
remains obscure, considering the drug's poor in vitro potency (MIC = 30-100 µg/mL). In the rabbit model of active
TB, an animal model that recapitulates the various lung lesion types observed in human TB disease, we showed
that PZA not only penetrates caseous necrotic lesions but also sterilizes them. In an ex vivo assay using caseum
from infected rabbits, we showed that PZA kills non-growing, drug tolerant Mtb. These findings provide an
explanation for the clinically observed treatment shortening effect of PZA: the drug reaches difficult-to-penetrate
TB lesions and kills recalcitrant `persister' Mtb. However, consistent with the modest in vitro potency of PZA,
onset of lesion sterilization is slow and concentrations required to kill Mtb in ex vivo caseum are high. Based on
these findings, the logical way forward is to improve the potency of PZA while maintaining its unique lesion
penetration and sterilization properties. To enable the rational optimization of PZA, we identified aspartate
decarboxylase PanD, required for coenzymeA biosynthesis, as a the first genetically, biochemically and
biophysically validated target of PZA. Consistent with poor whole cell activities of PZA, affinity of the drug (more
specifically its bioactive component pyrazinoic acid, POA) for PanD was in the µM range, confirming room for
improvement. Interestingly, mechanism of action studies revealed a novel antibacterial on-target mechanism
whereby, rather than inhibiting PanD's catalytic activity, binding of POA to PanD appears to trigger degradation
of the protein by the caseinolytic protease ClpC1.
Here, we propose to build on our discoveries and 1. fully characterize the novel on-target mechanism by which
the drug induces degradation of its target, 2. exploit in vitro pharmacological `sterilizing' models and PanD-based
assays for the discovery of novel PZA analogs with improved potency and sterilizing activity, and 3. characterize
lesion specific growth and replication status of PZA resistant panD mutant Mtb vs. wild type Mtb in the TB rabbit
model with and without PZA treatment.
In summary, we have identified key pharmacological properties responsible for the treatment shortening activity
of PZA in clinical settings, as well as the molecular target of the drug, and we propose a `first-in-class to best-in-
class' program to exploit these findings and rationally design the `next generation' PZA with improved sterilizing
activity.
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DOI:
10.1080/17460441.2023.2178413
发表时间:
2023-04
期刊:
EXPERT OPINION ON DRUG DISCOVERY
影响因子:
6.3
作者:
[Sarathy, Jickky Palmae, Aldrich, Courtney C., Go, Mei-Lin, Dick, Thomas]
通讯作者:
Dick, Thomas
DOI:
10.1021/acsinfecdis.6b00070
发表时间:
2016-09-09
期刊:
ACS infectious diseases
影响因子:
5.3
作者:
[Gopal P, Yee M, Sarathy J, Low JL, Sarathy JP, Kaya F, Dartois V, Gengenbacher M, Dick T]
通讯作者:
Dick T
DOI:
10.1021/acschembio.1c00131
发表时间:
2021-06-18
期刊:
ACS chemical biology
影响因子:
4
作者:
[Ragunathan P, Cole M, Latka C, Aragaw WW, Hegde P, Shin J, Subramanian Manimekalai MS, Rishikesan S, Aldrich CC, Dick T, Grüber G]
通讯作者:
Grüber G
DOI:
10.1016/j.bmcl.2013.07.006
发表时间:
2013-09-01
期刊:
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子:
2.7
作者:
[Dartois, Veronique, Barry, Clifton E., III]
通讯作者:
Barry, Clifton E., III
DOI:
10.1016/j.bmc.2022.117046
发表时间:
2022-11-15
期刊:
BIOORGANIC & MEDICINAL CHEMISTRY
影响因子:
3.5
作者:
[V. Hegde, Pooja, Aragaw, Wassihun W., Cole, Malcolm S., Jachak, Gorakhnath, Ragunathan, Priya, Sharma, Sachin, Harikishore, Amaravadhi, Gruber, Gerhard, Dick, Thomas, Aldrich, Courtney C.]
通讯作者:
Aldrich, Courtney C.
New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis
-
批准号:10613896
-
项目类别:
-
资助金额:$70.34万
-
财政年份:2019
-
负责人:Thomas Dick
-
依托单位:
New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis
-
批准号:10394991
-
项目类别:
-
资助金额:$73.5万
-
财政年份:2019
-
负责人:Thomas Dick
-
依托单位:
Combatting natural resistance and persistence in non-TB mycobacterial disease
-
批准号:10328930
-
项目类别:
-
资助金额:$90.67万
-
财政年份:2018
-
负责人:Thomas Dick
-
依托单位:
New drugs for non-tuberculous mycobacterial (NTM) lung disease in patients with cystic fibrosis
-
批准号:9923604
-
项目类别:
-
资助金额:$73.5万
-
财政年份:--
-
负责人:Thomas Dick
-
依托单位:
海外基金