Mechanism of membrane fusion involving the Gram-negative bacteria outer membrane
Project Number5SC1GM139701-04
Contact PI/Project LeaderKHAYAT, REZA
Awardee OrganizationCITY COLLEGE OF NEW YORK
Description
Abstract Text
PROJECT SUMMARY/ABSTRACT
Gram-negative bacteria constitute the majority of antibiotic resistant organisms identified as urgent threats to
human health by the Center for Disease Control and Prevention. A major reason why Gram-negative bacteria
are resistant to modern antibiotics is the impermeable nature of their outer membrane lipopolysaccharide (LPS)
layer. This impermeable nature is due to the strong lateral interaction between neighboring LPS molecules that
includes lipid A, the core saccharide, and the O-antigen. Nanotherapeutics capable of overcoming this barrier to
successfully deliver antibiotics to Gram-negative bacteria will be of immense importance for human health. It is
our intent to develop such nanotherapeutics by using the knowledge attained from delineating the mechanism
by which a Gram-negative bacteriophage fuses its external bacterial phospholipid (BPL) membrane with the
LPS of its host for initiating infection. Embedded into the Cystovirus BPL are multimeric protein complexes,
referred to as spikes, that recognize the Gram-negative host and perform fusion. These proteins are analogous
to, but different from, the better studied eukaryotic proteins responsible for membrane fusion (e.g. HIV env, West
Nile Virus glycoprotein E, and Herpesviridae gB protein). The intent of this proposal is to investigate the
mechanism by which spikes from three different members of the Cystovirus family recognize their hosts and
drive membrane fusion. The goals of this proposal are to determine the structure of the spikes for establishing a
structural scaffold for biochemical and biophysical studies (Aim 1), determine the mechanism of cellular
recognition (Aim 2), and determine the biochemical determinants responsible for LPS- BPL fusion (Aim 3). The
long-term goal of this project is to use the spikes for delivery of antibiotics to specific strains of pathogenic Gram-
negative bacteria.
Public Health Relevance Statement
PROJECT NARRATIVE
The proposed research is relevant to public health as it aims to overcome a major mechanism of antibiotic
resistance by Gram-negative bacteria -the exclusion of antibiotics by the lipopolysaccharide (LPS) outer
membrane. Our proposed studies seek to understand how a bacteriophage fuses its bacterial phospholipid
membrane with the LPS of its Gram-negative host. This research will have the potential to overcome the antibiotic
exclusionary properties of the LPS by generating phospholipid derived vesicles capable of targeting specific
strains of Gram-negative bacteria for delivery of antibiotics.
NIH Spending Category
No NIH Spending Category available.
Project Terms
Amino Acid SequenceAmino Acid SubstitutionAntibiotic ResistanceAntibiotic-resistant organismAntibioticsArchitectureAreaBacteriophagesBindingBiochemicalBioinformaticsBiophysicsCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeCommunicationComplexCryo-electron tomographyCryoelectron MicroscopyCystovirusDataEscherichia coliEukaryotaEukaryotic CellExclusionFamilyFamily memberFluorescence SpectroscopyGlycoproteinsGoalsGram-Negative BacteriaHIVHealthHerpesviridaeHorizontal Gene TransferHumanInfectionInvadedKnowledgeLateralLearningLifeLightLipid ALipopolysaccharidesMembraneMembrane FusionModernizationMolecular ConformationMolecular MachinesMultiprotein ComplexesMuscle CellsMyoblastsNatureNerveO AntigensOrganellesPathogenicityPeptidesPermeabilityPhospholipidsProcessPropertyProteinsPseudomonas aeruginosaPseudomonas syringaePublic HealthReportingResearchSalmonella typhimuriumSiteStructureSynaptic VesiclesSystemTechnologyTestingTherapeutic UsesVacuoleVesicleViralVirus DiseasesWest Nile virusX-Ray Crystallographyantibiotic resistant infectionsbacterial resistancebiophysical analysiseggmembernanotherapeuticpathogenpathogenic bacteriapathogenic fungusprotein complexrecruitscaffoldsperm cellstructural determinantsurgent and serious threat
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