User:Lizun Xin/Mtb BlaC Inhibition

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== Mechanism of Enzyme Inhibition ==
== Mechanism of Enzyme Inhibition ==
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[[Image:beta-lactam hydrolysis.png]]
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[[Image:amoxicillin hydrolysis edited.png]]
[[Image:Inhibition Mechanism.png]]
[[Image:Inhibition Mechanism.png]]
== Treatments ==
== Treatments ==

Revision as of 16:53, 31 December 2020

Drug resistant strain of Mycobacterium tuberculosis (Mtb) propose a major medical problem today, as traditional β-lactam antibiotics does not exhibited effective treatment. From previous study we understand that the resistance was due to the expression of protein in Mtb.

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Contents

Background on The Disease

Tuberculosis (TB) is a human respiratory disease, which is caused by bacteria: Mycobacterium tuberculosis (Mtb). The most common pathway of transmission for M. tuberculosis is by airborne droplets, for example, coughing and sneezing. M. bovis can be transmitted by animal products, for example uncooked meat and unpasteurised milk. The bacterium can hibernate in the human body for various times, from week to years. TB usually affects the lungs, but in some cases, the infection can spread outside of the lungs (eg. lymphatic system) [1].

As the infection in the lungs develops, patients may experience continuous coughing (sometimes with blood), chest pain and shortage of breath. if the secondary infection affects the immune system, the symptoms often show as fever, sweating and lost weight.

When the bacteria are in inactive state, TB does not have the ability to spread, however this proposes a problem for screening the disease. It is estimated that around 30% of the total population may be infected with the bacteria. However the rate of infection is relatively higher in developing countries which may be caused by rather poor medical facility and the knowledge of hygiene. Furthermore, patients with HIV seems to be more vulnerable to the infection, due to their compromised immune system. The standard screening of TB can be done by a chest X-ray. To further diagnose the infection often requires a sample of the patient’s mucus to test if they are TB positive and to differentiate if the strain is drug resistant.

The current treatment of TB is most likely to be done with giving combination of antibiotics and the patient mostly likely to be isolated. The only available vaccine available today is the BCG vaccine, which provides around 70% effectiveness

Discussion on the Drug Resistance

Multi-drug resistant (MDR) and extensively drug resistant strains (XDR) of M. tuberculosis propose a major threat in public health today. Currently, we lack effective treatment for the MDR and XDR strain Mtb. Existing β-lactam antibiotics can be ineffective, as the XDR Mtb is capable of hydrolysing these drugs.

The resistant XDR Mtb is mostly due to the expression of the β-lactamase enzyme, Ambler β-lactamase (BlaC). The BlaC active site is sufficiently large and flexible enable it to accommodate various β-lactams. As the size of BlaC active is relatively large, the desired inhibitor should possess strong hydrophobic characteristics.

The method of treatment was proposed, in order to treat XDR Mtb, the β-lactam need to be given in combination with a BlaC active site inhibitor. Therefore, β-lactam inhibitor can inhibit the BlaC active site and allowing β-lactams to inhibit cell wall synthesis and kill the Mtb-causing bacteria.

Mechanism of Enzyme Inhibition

Image:amoxicillin hydrolysis edited.png Image:Inhibition Mechanism.png

Treatments

Studying inhibitor potency to the BlaC active site, may allow us to design novel inhibitors. Previous studies suggest Clavulanate is not as effective as predicted when given in combination with cephalosporin. Therefore, better inhibitors for BlaC need to be designed so that the β-lactam antibiotics given in combination with them can more effectively destroy the bacteria.

Vaccination Programme

The vaccine effectiveness decreases as the recipient ages. BCG vaccine is not a part of the immune programme in UK and US, as TB is eradicated from those countries. Some other country gives BCG to children, to protect them from possible exposure from the adults.

References

[1]: M. Jones, R. Fosbery, J. Gregory and D. Taylor; Cambridge International AS and A Level Biology, Chapter 10: infectious diseases-Tuberculosis P209-211, 4th Edition, Cambridge University Press, 2014, ISBN: 978-1-107-63682-8

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Lizun Xin

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