Teixobactin

TEIXOBACTINFresh Hope in the War Against the Bacteria

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• NAME• REGESTRATION NO

Name Registration

Rachana Sarkar 12103022

Susmita Ghosh 12103023

Furhatun-Noor 12103048

Priyanka Florina Karmokar

12103050

Tajrian Rahman 12103059

Teixobactin….A New Antibiotic, Killing “Without Detectable Resistance ”

Teixobactin

Chemical Nature : Macrocyclic Depsipeptide

Discovered From Eleftheria terraeBacteria : Gram NegativeClass : B-proteobacteriaGenus : Aquabacteria

Antibacterial Activity Against •Excellent activity against Gram-positive pathogens,

including drug-resistant strains•Good activity against E. coli

asmB1

Mechanism of Action Cell wall inhibitor

Isolation Device Isolation Chip (iChip)

Compound Interest

Chemical Nature

Macrocyclic Depsipeptide

Molecular Formula

C58H95N15O15

Molecular Mass

1242.47 g/mol

Molecular Components

Four D-amino acids, Methylated phenylalanine, Enduracididine

Structure of Teixobactin

History

Discovered in : January 2015

Published in ‘Nature’

Lead Scientist : Prof. Kim Lewis

Research Institution

NorthEastern UniversityNational

Institutes of Health

Collaborative Pharmaceutical

NovoBioticsPharmaceuticals

Prof.Kim Lewis

How Teixobactin was Discovered?

From a Pile of Dirt

Discovered from :

Eleftheria terrae

Soil Source :

Grassy field of Marine soil

Isolation Device :

iChip (Isolation Chip )

Nutrient :

SMS or Molten agar

iChipThe Future of Antibiotic Discovery

iChip A hard piece of plastic with 192 tiny wells.75% of the ichip bacteria can be transferred and grown in lab.iChip may help scientists find new antibiotics from bacteria in marshlands, soil, and beyond

The Treasure Hunter Only about 1% of microbes in a soil & sea sample are able to

grow in the lab. The iChip expands that fraction to 50%

iChip

Diffusion Cham

ber

Petri Dish

0%5%

10%15%20%25%30%35%40%45%

Soil

Soil

iChip

Diffusion Cham

ber

Petri Dish

0%5%

10%15%20%25%30%35%

Sea Water

Sea Water

The Double Punch of Teixobactin

The Biosynthetic Gene Cluster

A. Genes (Non-Ribosomal Peptide Synthetase)

B. Domains

A=Adenylation, C=Condensation, T=Thiolation, MT=Methyl Transferase, TE=Thioesterase

C. Schematic Structure of Teixobactin

Nmphe- Ile-ser-Gln-Ile-Ile-Ser-Thr-Ala-End-Ile

Txo1 Txo2

A-MT-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-A-T-C-TE-TE

Nm Phe

Ile Ser Gln Ile Ile Ser Thr Ala End Ile

A New Class of Lipid-II Binding Antibiotic

Binding Sites of Teixobactin

The Functions of Target Sites

When Teixobactin Binds to Target Site

Lipid –II Precursor of peptidoglycan

Inhibits peptidoglycan

biosynthesis reactions

to make the thick walls around the cell)

Result :Bacterial wall comes

crumbling down

Lipid-III Precursor of cell wall teichoic acid

Inhibition of WTA biosynthesis steps

Prevents cell wall from breaking down

Result : Cell wall don’t rebuilt

Lipid-I (binds only in-vitro)

The intracellular form of the precursor

Probably less significant for

antimicrobial activity

Teixobactin…An Irresistible Newcomer…

How Do Bacteria Become Resistant?

Antibiotic Resistance now ‘Global Threat', WHO warns

Why Teixobactin is Irresistable?

The targets of Teixobactin are

not proteins but the lipids.

They are polymer precursors of

cell wall building blocks so

there is really nothing to mutate.

Bacteria without specialized

outer membrane can never

become resistant to Teixobactin. Teixobactin Resistance

Activity & Resistance Studies

A Comparison of Teixobactin's Activity

The effectiveness of

Teixobactin against

pathogenic bacteria.

By using MIC

(Minimum inhibitory

concentrations).

Determined by

Microdilution.

Bacterialcidal Activity Against Vancomycin Resistant S.aureus

Low Dose (4×MIC) for 27 Days.. Failed to Produce

Resistant Mutants

Toxic to Bacteria Cells But Non-Toxic to Mammalian Cells

ANIMAL STUDIES

TESTED AGAINST OBEJECTIVE RESULT

Mouse SepsisProtection Model

Clinical isolateS. aureus MRSA ATCC33591

Assess its in vivo bioavailability and PD50

Showed 100% efficacy against MRSA sepsis .

Mouse Thigh Infection Model

MRSA ATCC33591in a neutropenic mouse thigh infection model

Efficacy against MRSA in thigh infections.

Showed 100% efficacy against MRSA in thigh infections.

Mouse Lung Infection Model

Streptococcus pneumoniaeATCC 6301 in an immunocompetent mouse pneumoniamodel

Determine the compound’s potential to treat acute respiratory infections.

very active against S. pneumoniae in lungs.

‘Teixobactin vs Superbug’The Promising Antibiotic of Future

The Growing Antimicrobial Resistance in Bangladesh…Can Teixobactin Help Us?

This study reveals the growing antimicrobial resistance in Bangladesh.

Out of 122 isolates,

93.44% =intermediate

only 6.56% showed sensitivity.

In future, we can use Teixobactin against this 93.44% VISA.

93.44

6.54

% of S.aureus resistant,intermediate & sensi-tive to vancomcin

ResistantIntermediateSensitive

TEIXOBACTIN

Hopes Offered By Teixobactin

Teixobactin

Natural Antimicrobial Agent

From E.teeraeBy iChip

Molecular Modification

Semi-Synthetic

Synthetic

New Antibiotics

Teixobactin

No Genetic Resistance Appear

Effective Against Gram +ve Bacteria

C.difficile S.aureusM.tuberculosis

Teixobactin

Possible Therapeutic Uses

ColitisConjunctivitisTuberculosisMeningitisPneumonia

References :

Ling, L., Schneider, T., Peoples, A., Spoering, A., Engels, I., & Conlon, B. et al. (2015). A new antibiotic kills pathogens without detectable resistance. Nature, 517(7535), 455-459. doi:10.1038/nature14098

Lewis, Kim (7 January 2015). NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance. Cambridge, Massachusetts: NovoBiotic Pharmaceuticals. Retrieved 7 January 2015

Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A et al. (2010). "Use of ichip for high-throughput in situ cultivation of "uncultivable" microbial species". Appl. Environ. Microbiol.76 (8): 2445–50. doi:10.1128/AEM.01754-09. PMC 2849220. PMID 20173072.