A Brief History of TB
The TB bacterium was identified in the late 1800's, and shortly after a TB test was created. However, it was not until the late 1940s that an effective antibiotic for treatment of TB was available.
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Antibiotic Resistance and the Emergence of MDR-TB
Tuberculosis has existed for many centuries, but it was not until 1944 effective effective antibiotic therapy (streptomycin) became available. In 1950, scientist Renee Dubos predicted that that bacteria would eventually develop resistance to antibiotics through random mutations and natural selection
. Before long, it was found that some TB patients had strains of TB that were resistant to treatment with streptomycin. Over the next two decades additional anti-tuberculosis drugs were introduced, including p-aminosalicyclic acid, isoniazid, and rifampin, but as their usage increased, so did the appearance of TB strains that were resistant to one or more drugs. In 1956 strains of TB that were resistant to streptomycin, para-aminosalicylic acid (PAS), and isoniazid (INH) were discovered in Great Britain and were eventually dubbed multi-drug resistant TB or MDR-TB. In subsequent years, when strains with resistance to an even greater number of antibiotics were discovered, the term "extensively drug resistant TB" (XDR-TB) was coined.
Random Mutation and Natural Selection
Characteristics that provide resistance to treatment are initially introduced by random mutations that occur. The video below provides a brief description of how random mutations and natural selection work together to introduce new strains of résistant bacteria.
The likelihood that a new mutant strain with some degree of resistance to treatment with a particular antibiotic will survive is dependent on several factors.
- First, the mutation may confer some degree of resistance which is an advantage, but the same trait may have other negative consequence, such as a slower growth rate. The overall effect will depend on the magnitude of these changes and also on environmental pressures. For example, a mutation conferring both antibiotic resistance and a slower growth rate result in a net disadvantage in the absence of that particular antibiotic. However, if the bacterium exists within and individual being treated with the antibiotic to which resistance has developed, then the net effect is a distinct advantage over the other TB which are sensitive to the antibiotic. Antibiotic resistance a selection pressure, because susceptible bacteria will be killed if treated with a sufficient dose over a sufficient amount of time, but resistant bacteria will survive and have less competition for nutrients and space.
- A second factor is the rigor of treatment. Some mutations provide partial, but incomplete resistance to a drug. If an individual harboring such a mutant form is treated with an appropriate dose of antibiotic according to an appropriate dosing schedule and for a sufficiently long period to time, then the mutant is unlikely to survive. However, with sporadic or incomplete treatment, then the mutant is likely to survive.
- Thirdly, if a mutant organism becomes resistant to one drug, but remains sensitive to others, then treatment with multiple drugs will greatly reduce the likelihood that the new mutant will survive. This provided the rationale for using triple antibiotic therapy. Antibiotic resistance to MDR-TB and XDR-TB is becoming increasingly common as many TB patients are developing multiple strains of different mutant bacteria (mixed infection). Multi-drug treatment therapy is essential in order to effectively control and cure patients with multiple strains of bacteria. Administration of a single drug often is ineffective and results in the development of antibiotic resistance. Multi-drug therapies containing three to four different drugs are effective because they minimize the overall risk of resistance by simultaneously eliminating different strains of susceptible bacteria (CDC, 1993). Nevertheless, some strains have acquired traits that provide them with resistance to multiple drugs (MDR-TB and XDR-TB), creating an enormously challenging clinical problem.
In view of these observations, it is not surprising that individuals who are most at risk of acquiring MDR-TB are those who:
- Do not complete standard TB therapy as prescribed
- Develop TB again after a previous TB infection
- Come from MDR-TB endemic areas
- Live in close proximity with MDR-TB carriers
Mechanisms of Resistance
Strains of Mycobacterium tuberculosis have undergone a number of mutations that enable them to "resist" treatment with a number of antibiotics. The activity below lists a number of anti-TB drugs and the mechanism by which one or more strains of TB have become resistant.
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Roll over the tabs to see the mutations that are known to provide resistance to these anti-TB drugs. | |
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The video below is a 31 minute long lecture on mechanisms of antibiotic resistance.
Horizontal Gene Transfer
A bacterium that has acquired resistance to one or more antibiotics will transfer these traits to its offspring; this is referred to as vertical gene transfer (vertical evolution) which occurs when bacteria divide giving rise to two daughter cells by fission. However, resistance to antibiotics can also be spread through a process called horizontal gene transfer (HGT). HGT can occur via three transfer mechanisms:
- Conjugation- Direct cell to cell contact between two closely related bacteria, where plasmids (small DNA pieces encoded with the mutation) are transferred between cells.
- Transformation- Parts of DNA are taken up by the bacteria from the external environment. These DNA parts are the result of DNA death and lysis of other bacterium.
- Transduction- Bacteriophages (bacteria-specific viruses) transfer DNA between two closely related bacteria.