Mycobacterium tuberculosis

 M. tuberculosis was first described, as the causative agent of tuberculosis by Robert

Koch.it is an extraordinarily successful pathogen with a long history of afflicting humans.
Disease progression is a complex process, with only a small proportion of people exposed
becoming infected, and of those, the majority having latent infection during which the
bacteria may persist for decades in a metabolically inactive, or slowly replicating, state.
Estimates are that almost 2 billion people are latently infected, providing a global
reservoir of infection.

 Infection normally results in granuloma formation around the initial focus of infection,
and can lead to caseous lesions and cavity formation in active disease. Several complex
regulatory programs mediated by master genetic regulators are involved in switching into
this non-replicating state that can persist for long period of time.
  Mycobacterium tuberculosis (M. tb), also known as Koch's bacillus, is a species of
pathogenic bacteria in the family Mycobacteriaceae and the causative agent of
tuberculosis. It is is highly aerobic and requires high levels of oxygen. The high lipid
content of this pathogen accounts for many of its unique clinical characteristics. MTB can
withstand weak disinfectants and survive in a dry state for weeks.

 Mycobacterium tuberculosis is a slow-growing, chemoorganotrophic, non-motile, non-

spore-forming, aerobic bacillus. Under optimal laboratory conditions at 37 M.
tuberculosis doubles every 24 h, taking approximately 3 weeks to form buff-colored
rough colonies on agar plate.

 M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the
presence of mycolic acid. This coating makes the cells impervious to Gram staining, and
as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as
Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M.
tuberculosis with a microscope.

 Cells are curved rod-shaped and are often seen wrapped together, due to the presence of
fatty acids in the cell wall that stick together.

 M. tuberculosis is characterized in tissue by caseating granulomas containing Langhans

giant cells, which have a "horseshoe" pattern of nuclei.

-Phylum: Actinobacteria;
-Order: Actinomycetales
- Family: Mycobacteriaceae
-Genus: Mycobacterium
- Species: M. tuberculosis.
 Major spread is through air droplets originating from a person who has the disease either
coughing, sneezing, speaking, or shaking hands, making contact with toilet seats, sharing
food or drink, or sharing toothbrushes, can spread singing.it.

 When in the lungs, M. tuberculosis is phagocytosed by alveolar macrophages, but they

are unable to kill and digest the bacterium. Its cell wall is made of cord factor glycolipids
that inhibit the fusion of the phagosome with the lysosome, which contains a host of
antibacterial factors.

 Specifically, M. tuberculosis blocks the bridging molecule, early endosomal autoantigen

1 (EEA1); however, this blockade does not prevent fusion of vesicles filled with
nutrients. In addition, production of the diterpene is otuberculosinol prevents maturation
of the phagosome, the bacteria also evades macrophage killing by neutralizing reactive
nitrogen intermediates. More recently, M. tuberculosis has been shown to secrete and
cover itself in 1-tuberculosinyladenosine (1-TbAd), a special nucleoside that acts as an
antacid, allowing it to neutralize pH and induce swelling in lysosomes.

 In M. tuberculosis infections, PPM1A levels were found to be upregulated, and this, in

turn, would affect the normal apoptotic response of macrophages to clear pathogens, as
PPM1A is involved in the intrinsic and extrinsic apoptotic pathways. Hence, when
PPM1A levels were increased, the expression of it inhibits the two-apoptotic pathways.
With kinwomen analysis, the JNK/AP-1 signaling pathway was found to be a
downstream effector that PPM1A has a part to play in, and the apoptotic pathway in
macrophages are controlled in this manner As a result of having apoptosis being
suppressed, it provides M. tuberculosis with a safe replicative niche, and so the bacteria
are able to maintain a latent state for a prolonged time.
 Tuberculosis
 (TB) is an infectious disease usually caused by Mycobacterium tuberculosis.

 TB infection begins when the mycobacteria reach the alveolar air sacs of the lungs, where
they invade and replicate within endosomes of alveolar macrophages.

 Macrophages identify the bacterium as foreign and attempt to eliminate it by

phagocytosis. During this process, the bacterium is enveloped by the macrophage and
stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome
then combines with a lysosome to create a phagolysosome. In the phagolysosome, the
cell attempts to use reactive oxygen species and acid to kill the bacterium. However, M.
tuberculosis has a thick, waxy mycolic acid capsule that protects it from these toxic
substances. M. tuberculosis is able to reproduce inside the macrophage and will
eventually kill the immune cell.

 The primary site of infection in the lungs, known as the Ghon focus, is generally located
in either the upper part of the lower lobe, or the lower part of the upper lobe.

 Tuberculosis is classified as one of the granulomatous inflammatory diseases.

Macrophages, epithelioid cells, T lymphocytes, B lymphocytes, and fibroblasts aggregate
to form granulomas, with lymphocytes surrounding the infected macrophages. To the
naked eye, this has the texture of soft, white cheese and is termed caseous necrosis.

 Tuberculosis generally affects the lungs, but it can also affect other parts of the body.
Most infections show no symptoms, in which case it is known as latent tuberculosis.

 Around 10% of latent infections progress to active disease, which, if left untreated, kill
about half of those, affected.
Typical symptoms of active Tb are:
 Chronic cough with blood-containing mucus, fever, night sweats, and weight loss,
lymphadenopathy. It can be spread through air when patient has active tb when patient
split sneeze or cough. Active infection occur mostly in people who smoke or have
HIV .so they are the most common risk factors.

 Tuberculosis may infect any part of the body, but most commonly occurs in the lungs
(known as pulmonary tuberculosis. Extra pulmonary TB occurs when tuberculosis
develops outside of the lungs.
Therefore, we have

Pulmonary:
 Symptoms may include chest pain and a prolonged cough producing sputum.
Occasionally, people may cough up blood in small amounts, and in very rare cases, the
infection may erode into the pulmonary artery or a Rasmussen's aneurysm, resulting in
massive bleeding. The upper lung lobes are more frequently affected by tuberculosis than
the lower ones. It may become chronic illness making scar in upper lobes.

Extra pulmonary:
 Notable extra pulmonary infection sites include the pleura (in tuberculous pleurisy), the
central nervous system (in tuberculous meningitis), the lymphatic system (in scrofula of
the neck), the genitourinary system (in urogenital tuberculosis), and the bones and joints
(in Pott disease of the spine), among others. A potentially more serious, widespread form
of TB is called "disseminated tuberculosis", it is also known as military
tuberculosis.Miliary TB currently makes up about 10% of extra pulmonary cases.

Diagnosis:
 Diagnosing active tuberculosis based only on signs and symptoms is difficult, as is
diagnosing the disease in those who have a weakened immune system. A diagnosis of TB
should, however, be considered in those with signs of lung disease or constitutional
symptoms lasting longer than two weeks. A chest X-ray and multiple sputum cultures for
acid-fast bacilli are typically part of the initial evaluation. A definitive diagnosis of TB is
made by identifying M. tuberculosis in a clinical sample like sputum, pus, or a tissue
biopsy.

 Blood tests to detect antibodies are not specific or sensitive, so they are not recommended
ANTImycobcteruim tubtculosis agent:

 The recommended treatment of new-onset pulmonary tuberculosis is six months of a

combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and
ethambutol for the first two months, and only rifampicin and isoniazid for the last four
months. Where resistance to isoniazid is high, ethambutol may be added for the last four
months as an alternative. Treatment with anti-TB drugs for at least 6 months results in
higher success rates when compared with treatment less than 6 months, even though the
difference is small.

Drug resistance:
 Primary resistance occurs when a person become infected with a resistant strain of TB. A
person with fully susceptible MTB may develop secondary (acquired) resistance during
therapy because of inadequate treatment, not taking the prescribed regimen appropriately
(lack of compliance), or using low-quality medication.[115] Drug-resistant TB is a
serious public health issue in many developing countries, as its treatment is longer and
requires more expensive drugs. MDR-TB is defined as resistance to the two most
effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is
also resistant to three or more of the six classes of second-line drugs.
Explanation of Drug Resistance in M. tuberculosis:
1. Spontaneous Mutation:
. Explanation: M. tuberculosis has a high mutation rate during replication, leading to
spontaneous mutations in its genome.

• Implication: Some mutations confer resistance to antimycobacterial agents, allowing

the survival of drug-resistant strains.

2. Incomplete Treatment Courses:

• • Explanation: Inadequate completion of prescribed antibiotic courses can

lead to the survival of partially treated bacteria.

• Implication: Surviving bacteria may develop resistance, making subsequent

treatments less effective.

3. Poor Adherence to Treatment:

• Explanation: Patients may fail to adhere to the prescribed treatment

regimen, leading to suboptimal drug levels.

• Implication: Suboptimal drug concentrations promote the survival of resistant

strains, contributing to the development of drug resistance.

4. Transmission of Resistant Strains:

•• Explanation: Person-to-person transmission of drug-resistant strains can occur,
spreading resistant forms of M. tuberculosis.

• Implication: The prevalence of drug-resistant strains increases, posing challenges for

treatment and control efforts
First Line

Rifampin
Isoniazid
Pyrazinamide
Ethambutol

Second Line
Kanamycin (discontinued use in the USA)
Streptomycin
Capreomycin
Amikacin
Levofloxacin
Moxifloxacin
Gatifloxacin
MDR-TB
Bedaquiline
Delamanid
Linezolid
Pretomanid
We can divide drugs as:
 Cell wall inhibitors (isoniazid, ethambutol, ethionamide, cycloserine), nucleic acid
synthesis inhibitors (rifampicin and quinolones), protein synthesis inhibitors
(streptomycin, kanamycin) and inhibitors of membrane energy metabolism
(pyrazinamide).

 Isoniazid (INH) is the most widely used treatment for TB and its latent infections15.
This drug enters the cell as a pro-drug, which is activated by MTB catalase-peroxidase
enzyme (KatG). The enzyme activates INH and facilitates its interaction with various
toxic reactive species (oxides, hydroxyl radicals and organic moieties) in the bacterial
cell16, thereby, weakening the components of the cell wall and finally, the death of the
bacteria.

 Rifampicin (RIF) have been used as first-line drug in combination with other therapies
for the treatment of TB infections. RIF is believed to inhibit bacterial DNA-dependent
RNA polymerase9. This drug interferes with RNA synthesis by binding to the β subunit
of mycobacterial RNA polymerase, which is encoded by rpoB, thereby killing the
organism.

 Ethambutol (EMB) is a first-line drug used in combination with INH, RIF and PZA
preventing the emergence of drug resistance mycobacterium. This drug interferes with
the cell wall of MTB through a synthetic mechanism thereby inhibiting arabinosyl-
transferase (embB), an enzyme involved in cell wall biosynthesis.

 Aminoglycosides (Streptomycin, Kanamycin, Amikacin)

Aminoglycosides exert their action by binding to the 30S subunit of ribosomes and
inhibiting the protein synthesis of the mycobacteria
  Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin)
Fluoroquinolones exert their effects by inhibiting DNA gyrase and topoisomerase IV, further
inhibiting DNA synthesis within the bacteria.
Challenges Associated with M. tuberculosis Infections:
1. Latent Infections and Reactivation:
Challenge: Individuals with latent tuberculosis may additionally later experience
reactivation, main to energetic ailment.
Impact: Identifying and treating latent infections are tough, requiring effective techniques
for screening and preventive therapy.
3. Complex Treatment Regimens:
Challenge: Treatment of tuberculosis regularly involves a couple of antimycobacterial
marketers and prolonged guides.
Impact: Complexity can lead to poor adherence, remedy interruptions, and expanded risk
of drug resistance.
4. Social Stigma and Barriers to Care:
Challenge: Social stigma related to tuberculosis may additionally discourage individuals from
looking for timely hospital treatment
5. Limited Access to Healthcare:
Challenge: Limited access to healthcare offerings hinders early prognosis and treatment
initiation.
Impact: Delayed care exacerbates the severity of tuberculosis, increases the danger of
complications, and contributes to the unfold of the sickness.

REFRENCESS:
Author: National Institute of Allergy and Infectious Diseases (NIAID)

Title: "Mycobacterium tuberculosis"

Date: April 19, 2016

URL:
1. Furin, J.; Cox, H.; Pai, M. Tuberculosis. Lancet 2019, 393, 1642–1656. [Google Scholar]
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