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From their accidental discovery by Professor Alexander Fleming in 1928 and subsequent isolation by Ernst Chain and Howard Florey ten years later, antibiotics have gone on to change the face of medicine. It was heralded as the wonder drug when upon mass production; it was used to cure most of the bacterial infections that broke out amongst the troops on D-Day1. Unfortunately, antibiotics are now overused at such a rate that the bacteria they were designed to combat are becoming resistant; which begs the question is this the end of an era?
Bacterial resistance to antibiotics is a topic that has gripped the nation's conscience for the last few years. Outbreaks of so called superbugs such as MRSA (Methicilin resistant Staphylococcus aureus) and Clostiridium difficile, (which is resistant to TWO different types of antibiotics) have left many patients in hospital anxious about their stay. Hospitals, filled with sick people with weak immune systems and without competing bacteria (which are killed off by broad spectrum antibiotics) are a breeding ground for resistant bacteria including: E-coli, Salmonella, Pseudomonas aeruginosa and Streptococcus.
A key attribute of microbial evolution is a string of adaptive mutational changes that take place in sweeps whenever fitter mutants overcome the resident population2. Taking Escherichia coli (E-coli) as an example, Dr Lucinda Notley-McRobb's team at the University of Sydney analysed continuous cultures at two loci (separate sites). Mutations at these loci produced advantageous phenotypes such as improved transport under glucose limited conditions.
Three separate sets of changes which altered the frequency of neutral mutations were also found to cause phage T5 resistance. We can therefore correlate a reduction in the number of neutral mutations with T5 resistance.
As well as reduced neutral mutations, two of these multi-step changes resulted in the subsequent formation of at least 13 different alleles at the 2 loci (mgl and mlc). These different alleles lead to variations at the mgl and mlc loci known as polymorphisms. The fact that these variants represented many different mutations in the population suggests polymorphisms were not the result of a mutator or directed mutation event2.
The third sweep showed a rather more distinct result which alternated between T5 resistance and the advantageous mgl mutation.
This so called hitchhiking was congruent with an increase in the rate of mutations which reflected the presence of a strong mutation in the population.
These examples of sporadic selections between the two states allows the maintenance of a great deal of genetic diversity, even in a rapidly evolving culture, "with no individual "winner clone" or genotype purging the population"2.
It is this genetic diversity and the presence of so many polymorphisms coupled with the rapid changing nature of the bacterial genome that allows bacteria to adapt to changes in antibiotic properties, thus leading to antibiotic resistance.
Antibiotics work by binding to a protein within the bacteria which disrupts its proper function. Bacteria on the other hand get round this problem by mutating the genes that code for this protein, creating an altered protein which can no longer be bound by the antibiotic. Natural selection therefore favours this particular strain in the presence of the antibiotic, as this mutant will survive where other competing organisms won't.
Another way bacteria can evade the action of antibiotics is via the mechanism of horizontal gene transfer. Unlike humans, bacteria can swap DNA via conjugation; a process where bacteria fuse and exchange genetic information. This allows the fast acquisition of resistance genes by all members of the population and hence a greater increase in infection, with antibiotics having little or no effect.
This mechanism of natural selection and mutations is the driving force of microbial evolution. Evolution is concerned with the gain of functional elements as well as loss of function mutations, with the acquisition of advantageous traits and subsequent spread through the population proving very beneficial.
It is therefore clear that bacteria benefit from the acquisition of an antibiotic resistant gene and that the action of such a gene can be seen in the presence of said antibiotic. However, is there a fitness cost exerted on the bacteria in the absence of the antibiotic? If so, then this can be exploited to combat the problem (see figure 1).
One way to deal with antibiotic resistance is to stop the use of that particular antibiotic until resistance genotypes are removed or reduced from the population. Professor Richard Lensky of the University of Michigan argues that "resistant genotypes are less fit than their sensitive counterparts in the absence of antibiotic, indicating a cost of resistance"3.
Antibiotic resistant bacteria (AR) with red phenotype competes with its antibiotic sensitive counterparts 1.
In the presence of antibiotics, growth of sensitive bacteria will be inhibited, which results in colonization by AR bacteria 2.
The resistant bacteria will proliferate to dominate the bacterial population 3.
Once the antibiotic is removed, the resistant bacteria may remained if its remnants are not costly or it may be maintained in the environment if they have acquired compensatory mutations 4.
Otherwise, the resistant population may disappear, and the ecosystem will return to the original steady-state scenario 1.
Figure and legend sourced from: Nature Reviews Microbiology 5, 958-965 f(December 2007)
However these results need to be approached with a little bit of scepticism as experimental studies introduce resistant genes to bacteria that don't have the natural mutation. And so there is no evolutionary history of that bacteria being associated with antibiotic resistant genes.
If resistance has an evolutionary association in the bacterial genome, does this mean there is an evolutionary adaptation to overcome the cost incurred as a result of resistance? Several experiments (in vitro and in vivo) have shown the side effects of resistance can be substantially reduced or even completely eliminated by evolutionary changes in bacteria over rather short periods of time; thus making it more difficult to eliminate resistant genotypes in the bacterial population simply by suspending the use of antibiotics3.
One of the primary reasons for the rise in antibiotic resistance is the sheer volume of numbers prescribed. Either as a result of patients insistence, doctors not having the time to explain why they wouldn't work. For example a third of people think antibiotics are useful against the common cold5.
So next time you need antibiotics, think about which side you're fighting for!