Tuberculosis every 106 to 108 replications, wild strains

Tuberculosis (TB) is an infectious disease caused by the Mycobacterium tuberculosis, which can invade various organs, especially the lungs. Tuberculosis can enter the body
along a grain of dust or splashing of droplets that spread during coughing or
sneezing19. Six countries contributing the largest TB include India, Indonesia,
China, Nigeria, Pakistan and South Africa. The bacteria that cause TB can
develop resistance to antimicrobial drugs used to treat the disease.
Multidrug-resistant TB (MDR-TB) is a TB which can not be treated by at least
two of the potent first line anti-TB drugs, isoniazid and rifampicin. Global
efforts to further enhance the detection of the case and treatment
for MDR-TB is urgently needed. In the year 2013, only 45% of the estimated
300,000 cases of patients with MDR-TB were detected among all pulmonary TB
around the world. About 5% of cases of MDR-TB that are either not detected or
managed outside the national TB programs were not reported25.

 

Comparative genomic analyses drug resistance on MTB caused by
chromosonal mutations that required for the action of antibiotics, gene that
encodes the protein targets of drugs applied, or enzymes that are required to
activate pro-drug. Because the target of antibiotics is important to cell
function, resistant mutations encodes gene target will affect pathogenesis15. In every 106 to 108
replications, wild strains of MTB undergo spontaneous mutations that confer
resistance to a single drug.

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Table 1.Mutations in antibiotic19

Drug

Average
mutation rate

Isoniazid

2.56 x 10-6

Rifampicin

2.25x 10-10

Ethambutol

1 x 10-7

Streptomycin

2.95 x 10-8

Pyrazinamide

1 x 10-3

 

Rifampicin (RIF) is a critical component of first-line therapy for TB
which has fast onset when contact with MTB3. Almost 90% of RIF resistant strains are also resistant to isoniazid
and resistance to RIF is used as surrogate marker for detecting MDR TB2. RIF resistant is caused by mutation of a single
nucleotide-substitution on rpoB region, gene that encodes the ?-subunit of RNA
polymerase to the DNA-dependent (RNAP) (ilse du). Transcription of the RNAP by
the rpoB mutations in the gene have various effects on the physiology of the
MTB, also mutations in this site can caused secondary mutations which lead
resistance to another antibiotic9.

 

Autophagy is a complex process involving multiple protein consisting of
complex formation and initiation of double membrane development phagophore as
nucleation, elongation of the membrane and completion of autophagosome vesicles
surround the cargo, and then they will fuse with lysosom. Lysosom contain
hydrolase that can degrade and dispose component18. MTB persist and mutiply within
infected macrophage, where it resides in host-derived phagosome which fails to
fuse with lysosom10. Autophagy caused by metabolic and immune signals consists of
recognition of pathogen and stimulation by pro-inflammatory cytokines.
Autophagy trigger microtubule-associated proteins 1B light chain 3B
(MAP1LC3B/LC3), a protein encoded by the gene MAP1LC3B in humans25. LC3 was first identified as a
protein co-purified with microtubule-associated protein 1A and 1B from rat brains.
This protein is derived from 28% of amino acids with Apg8/Aut7p who plays a
role in autophagy in yeast, undergoes complex C-terminal proteolitic and lipid
(phosphathydil ethanolamine) modifications, which is translocates from cytosol
to the autophagosomal membrane12.