Functional characterization of HtrA, an essential mycobacterial protease
Functional characterization of HtrA, an essential mycobacterial protease
批准号:
9319407
负责人:
Katherine J Wu
金额:
$3.67万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2020-08-31
关键词:
Amino AcidsAntibiotic ResistanceAntibioticsAntimycobacterial AgentsAttenuatedBacteriaBindingBiochemicalBiochemistryBiological AssayCause of DeathCell CycleCell Cycle RegulationCell WallCell physiologyCellsChemicalsComplexCytoplasmic TailDataDefectDiseaseDrug TargetingDrug resistanceDrug resistance in tuberculosisEnvironmentEnzymesExhibitsFutureGeneticGenus MycobacteriumGrowthHumanImaging TechniquesImmuneInfectionKineticsKnowledgeLengthMethodsMicroscopyMorphologyMulti-Drug ResistanceMycobacterium tuberculosisNaturePathway interactionsPeptide HydrolasesPeptidoglycanPharmaceutical PreparationsPharmacologic SubstancePhenotypePhysiologyPlayPopulationPrecipitationProtein translocationProteinsRecording of previous eventsRecruitment ActivityRegulationRoleSerineSerine ProteaseStressSystemTestingTimeTuberculosisVariantVirulenceWorkattenuationbasebiological adaptation to stresscombatdrug developmenteffective therapyexperimental studygenetic approachglobal healthinsightmycobacterialnew therapeutic targetnovelpathogenperiplasmpressurepreventresilienceresistant strainresponsestress tolerance
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
Tuberculosis is a leading cause of death worldwide, infecting 1/3 of the global population. However, the
complex chemical composition of the mycobacterial cell wall, robust resilience of Mycobacterium tuberculosis
(Mtb) in harsh host environments, and ever-increasing rates of antibiotic resistance have hindered effective
treatment of this disease. Mycobacterial proteases, while understudied, represent a class of potential novel
drug targets due to their well-conserved nature and importance to cellular physiology. Although the highly
conserved serine protease HtrA is dispensable for growth in most other bacteria, Mtb appears to require HtrA
activity in multiple contexts. Broadly, this proposal seeks to define how the various functions of HtrA contribute
to 1) Mtb's response to environmental stress and 2) the regulation of the mycobacterial cell cycle. Aim 1
interrogates HtrA's role in the mycobacterial stress response, taking a genetic approach to delineate the
functions of each of HtrA's domains. In this aim, I will assess the contributions of HtrA's unique cytoplasmic
domain and its serine-based proteolytic activity, using a combination of genetics and biochemistry to identify
HtrA's binding partners and substrates. Aim 2 investigates HtrA's non-proteolytic role in cell cycle regulation,
using multiple complementary strategies to identify cell wall enzymes with which HtrA interacts and define the
cell cycle pathways in which HtrA operates. To accomplish this, I will validate putative HtrA binding partners at
the cell wall interface, track HtrA kinetics with time-lapse microscopy, and uncover HtrA's genetic interactions
with pathway-specific drugs. Together, these aims define HtrA in two different contexts – as a protease crucial
for combating environmental stress and as a novel cell cycle regulator. This work will provide insight into the
unprecedented essentiality and diverse functions of mycobacterial HtrA, as well as the unique mechanisms
that govern the growth and survival of Mtb. Ultimately, this work has the potential to fill large gaps in knowledge
of Mtb's persistence in the context of human infection and provide novel targets for antimycobacterial drugs.
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