Origin and Evolution- A Neck to Neck Race
Tuberculosis (TB) is a highly contagious disease that transmits through droplet nuclei. When an infected person coughs, talks, or sneezes, the aerosols containing Mycobacterium tuberculosis (MTB) spread in the air. Inhalation of these particles allows the bacilli to enter the lungs of a healthy individual, thus making the lungs the primary target organ. Although curable in nature, the disease can often become life-threatening if proper and timely treatment is not received. The emergence of drug resistance (DR) that is, the inability of prescribed drugs to kill the bacteria is a major factor that brings about TB-associated deaths.
TB has been inﬂicting humans since time immemorial, but it was not until the 1940s that drugs to kill MTB came into the picture. Within the very next decade, however, some bacteria stopped responding to the drugs used. Streptomycin was a drug of choice at that time and through random mutations, and natural selection few MTB strains developed resistance to it. In the following decades, newer anti-TB drugs like isoniazid (INH), rifampicin (RIF), and P-aminosalicylic acid (PAS) were developed. As if to keep up with the pace of our advances in drug designing, MTB also evolved and found ways of becoming resistant to each of them.
Eventually, MTB started to get an upper hand when it could simultaneously show resistance to multiple anti-TB drugs. Such strains of MTB that resist at least INH and RIF are called multi-drug resistant (MDR). Strains that developed resistance to newer anti-TB drugs and antibiotics developed in the after decades, in addition to INH and RIF were dubbed extensively drug-resistant (XDR). It does not stop at this, as eventually, strains showed resistance to both ﬁrst and second-line anti-TB drugs, and the term extremely drug-resistant (XXDR) or totally drug-resistant (TDR) was coined.
|MDR||Resistance to isoniazid and rifampicin, with or without resistance to other ﬁrst-line drugs (pyrazinamide, ethambutol)|
|XDR||MDR plus resistance to any ﬂuoroquinolone (ciproﬂoxacin, oﬂoxacin, levoﬂoxacin, moxiﬂoxacin, levoﬂoxacin, gatiﬂoxacin, sparﬂoxacin), and to any of the three second-line injectables (amikacin, capreomycin, kanamycin)|
|XXDR or TDR||Resistance to all ﬁrst-line anti-TB drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) and second-line anti-TB drugs (levoﬂoxacin, moxiﬂoxacin, bedaquiline, delamanid, linezolid)|
What intrigues human minds is; how bacteria, barely a few micrometers in size, could give tough time to scientists across the world. How MTB plays its cards to become unresponsive to anti-TB drugs can be understood to a large extent by looking at the below-mentioned mechanisms
Innate resistance– Constituents of the cell wall make it less permeable to the drug, affecting the accessibility of the target. Likewise, efﬂux pumps remove drugs that could cross the cell wall and the enzymes produced by the organism can modify drugs. In addition to these, MTB can modulate its gene expression so that it can adapt to the effect/presence of the drugs. Slow growth rate, dormancy, and metabolic shutdown are seen in some strains called persisters. These can become phenotypically tolerant to drugs, even in absence of genetic mutations.
Vertical transmission– During replication, an error may occur spontaneously in the DNA code. This is known as random mutation. This leads to a change in genetic code and in turn the associated characteristic of bacteria which may either be advantageous or disadvantageous to it. Strains may get the ability to resist antibiotics and thus can multiply or become susceptible and get killed. Primary DR usually occurs because of single nucleotide polymorphisms and insertion-deletion in the gene coding for drug targets. Although single-step chromosomal mutations are more common, stepwise acquisition and ﬁxation of mutations resulting in a gradual increase in resistance are also reported.
Horizontal transmission– Plasmids and transposons can be transferred between bacterial cells. When genes conferring DR are present in any of them, they can transfer it to other bacterial cells and give them the same ability. However, this type of transmission is rare in MTB and is not consistently seen.
Triggering Factors- Adding Fuel to the Fire
Along with the mechanisms adopted by MTB, certain contributing factors act in their favor allowing them to more easily develop resistance. A few of them are-4,6
Alteration in the DNA repair system– can reduce the ability to repair DNA damage, resulting in increased mutation rates. These mutations in turn will increase the bacteria’s chances of developing DR and enhance survivability.
Over-expression of efﬂux systems– Mutations in regulatory genes and exposure to antibiotics can induce drug efﬂux pumps in MTB. Contrary to the high-level resistance seen in gene mutations, increased activity of efﬂux systems reduces intracellular levels of antibiotics conferring low-level resistance.
Non-compliance to TB therapy– Certain mutations impart partial or incomplete resistance to a drug. Correct drug dosage, appropriate dosing schedule, and sufﬁcient treatment period are required to kill such bacterial strains. But, incomplete course, irregular schedule, wrong dosage, inadequate length of time, and other factors make such mutants more likely to survive.
Mixed infection– An infected individual may harbor more than one bacterial strain. It usually happens when people live in close proximity with MDR patients/ carriers or come from TB endemic areas. Individuals that develop TB again after being treated for the disease in the past may also have mixed strains. Multi-drug treatment therapy (3 or 4 drugs) can effectively control and cure such patients. Administration of drug combinations minimizes the risk of resistance development as well as eliminates different strains of bacteria simultaneously.
Adaptation in Human Lung Environment- Fight for Survival
Patients may get DR MTB infection in two ways.5
- Due to the infection with a DR MTB strain which is called as Primary DR
- Because of the mutations caused by treatment failure of susceptible strains which eventually become resistant
Metabolic adaptation to the host lung environment plays a signiﬁcant role in the latter type. MTB has evolved to infect and persist in the host over the years. Having higher hydrophobicity than other Mycobacterium spp. is advantageous for its transmission through aerosolization. Once MTB gains entry into the respiratory system, it comes across different host lung micro-environments which can on some occasions be extracellular (like in the initial phase it comes in contact with alveolar lining ﬂuid before interaction with alveolar phagocytes and immune cells, after escaping from necrotic cells or after re-activation in cavities). Here, MTB adapts in the extracellular microenvironment. Whilst intracellular adaptation occurs in the alveolar phagocytes (during primary infection) and within the alveolar macrophages in granulomas (during the latent stage). The organism, thus, adapts its metabolism within the host’s lungs to evade attack of the immune system in order to survive and establish an infection (active or latent). The cell envelope of the bacterium also provides structural support to withstand osmotic changes. The protein component of the cell wall regulates permeability to drugs and hence, has implications for drug resistance. Furthermore, some proteins of the cell wall may directly act on drugs to inactivate it. Not limiting to this, the cell envelope also plays an immunomodulatory role in the bacterium-host crosstalk with key implications in pathogenesis and drug resistance development.
Persistence of Untreatable Strain- A Global Threat
Earlier it was believed that TB infections with DR strains would be self-limiting. But in recent years, a large sum of TB patients were found infected with primary MDR-TB. If the main cause of resistance was inadequate or irregular treatment, slowly acquired resistance should have been reported instead. This indicates that TDR strains being untreatable may continue to circulate and spread in the community.
Certain areas like crowded healthcare centers, which cannot be avoided, act as hubs for the spread of resistant strains. Nosocomial transmissions can be afﬁrmed as drivers of the epidemic, especially among immuno- compromised individuals. Not to forget, the risks imposed on health workers of contracting TDR strain infections.
Making a Difference
One person succumbs to TB every 21 seconds.5 This single airborne pathogen is the leading killer worldwide currently, after COVID. The peculiar behavior of MTB in resisting almost every new drug developed to do away with it has made it a burning global concern, raising the need to religiously stick to all possible measures that can prevent it from developing resistance. Although innate mechanisms of the bacteria causing DR may not always be controllable, taking care of man-made triggering factors alone can reduce the brunt of resistance development.
Compliance with Prescription Meds- A Small Requirement for Great Results!
A 35-year-old male residing on the outskirts of a city had intermittent fever with malaise and cough for quite some time. He had also lost some weight over the same span. Assuming it to be work pressure and stress-related general illness, he kept on delaying his visit to the doctor. It became all scary on the day when he saw that his sputum was blood-laden. This is when he rushed to his doctor without waiting even a single minute. After examinations and investigations, he was diagnosed with TB and was put on anti-TB drugs. Although advised to strictly adhere to the therapy for 6 months, he took it lightly when he started feeling better and the symptoms disappeared. He thought that the healthy diet and lifestyle which he is maintaining as suggested by his doctor would do the wonders and boost his immunity, and he should moderate the medicines prescribed. Then started the downfall, within the next six months he was back to the doctor with drug resistance. The whole point of trying to avoid medicines was in vain, as he had to start the treatment again and with the additional stronger medicines.