Antibiotic Resistance in M.tuberculosis

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Development of resistance in M .tuberculosis is a depiction of Darwin’s theory of evolution “survival of the fittest”. Due to selective pressure caused by antibiotics, M. tuberculosis comes up with survival mutants. Combination therapies have created the evolution of strains, eventually, causing resistance to all available drugs. Also, the exposure to bactericidal antibiotics is resulting in an induced mutation which ends up promoting mutant MDR phenotypes. Drugs like isoniazid and ethionamide are prodrugs that work cytotoxically after activation by redox enzymes in the bacterial cytoplasm. This process produces reactive oxygen and radicals that kill the bacterial cell, if they fail to kill, they eventually turn into bad promoting mutagenesis that ends up producing multidrug resistance.

There are some specialized mechanisms that help in detoxifying drug molecules that become able to penetrate the cytoplasm of bacteria. They can be enlisted as:

•       Target alteration
•       Target mimicry
•       Drug modification
•       Drug degradation
•       Drug efflux

Target alteration:

Target alteration is one of the methods that bacteria use to escape from drug molecules. This method is used by M.tuberculosis, for example, in the case of macrolides, these drugs bind to a specific site on the 50S subunit of ribosomal RNA of bacteria, which bacteria alter by methylating thus reducing the binding affinity of the drug that results in the reduction of inhibitory activity of the drug.

Target mimicry:

Target mimicry is a fascinating way used by bacteria to avoid Abx targets. It was proposed that bacteria sequester Abx in the mycobacterial cytoplasm by mimicking the structure of DNA, in result, freeing the DNA from the Abx target. Bacteria have done this with the aid of other structures, for example, in the case of fluoroquinolones there is a protein MfpA in M.tuberculosis that holds the fluoroquinolones from its target action because of its structural resemblance with DNA double helix.

Drug modification:

Many mycobacterial species can directly inactivate drugs to escape target action through several chemical modifications like acetylation. For example, in the case of aminoglycoside (an important anti-TB drug since old times) the resistance in M. tuberculosis comes from an acetyltransferase named as enhanced intracellular survival (esi) that manipulates host innate immunity against infection.

Drug degradation:

Bacterial species including M. tuberculosis use another way to escape Abx which is drug degradation by mechanisms like hydrolysis. For example, for β-lactams, the mycobacterium uses a hydrolytic enzyme hydrolyze the β-lactam ring in these drugs which results in the degradation of the drug leaving bacteria free from the Abx target.

Drug efflux:

Drug efflux is the most common method used by bacteria to avoid Abx. In this method, bacteria expel the drug out of the cytoplasm through an efflux pump with the aid of transporters in the transmembrane. For example, Tap is a transporter responsible for the efflux of aminoglycoside, streptomycin, tetracycline, and PSA in Mycobacterium.