Antibiotic resistance: Evolution in action?
The discovery of antibiotics was one of the most important advances in medicine, profoundly improving human health. Many bacterial infections (for example, tuberculosis and wound infections) that often killed people became treatable, saving millions of lives.
In the 15 years or so following their introduction in the 1930s, deaths in the USA, for example, declined by about 220 per 100,000 population per year. All other medical technologies only reduced deaths by about a further 20 over the next 45 years.1
However, the development of resistance to antibiotics threatens this success. Globally, infections caused by bacteria resistant to many or all of the currently available antibiotics are increasing. Furthermore, fewer companies are working to develop new antibiotics. In 1990 there were 18 companies, whereas in 2011 there were only four.2 A major reason for this decline is the realization that resistance soon follows the introduction of a new antibiotic, and it costs a lot of money to develop new ones. The discovery of a new class of antibiotics, announced in 2015, was the first since 1987.3
Biology texts used in schools and universities often present antibiotic resistance as an example of ‘evolution in action’, supposedly proving that microbes could change into microbiologists over billions of years. However, studies of the biochemical mechanisms that underlie resistance show that the development of resistance gives no support to such ‘big picture’ evolutionary changes. The types of change discovered support a creationist view of life, that natural changes are limited and cannot change one basic kind of organism into another.
The mechanisms of resistance
Scientists have discovered three general categories of resistance:
- Alteration or protection of the target of the antibiotic
- Restriction of the drug’s access to the target
- Inactivation of the antibiotic.
1. Alteration or protection of the target
Colistin (otherwise known as polymyxin E) provides an example. In the body, colistin is a positively-charged molecule that attaches to negatively-charged molecules (lipopolysaccharide or LPS) present in the outer membrane of certain bacteria (Gram-negative bacteria). This binding is an essential first step in the process that kills the bacteria.
Mutations in one particular bacterium prevent the production of LPS. This therefore prevents colistin from binding to—and therefore killing—the bacterium.4
There are more complex mechanisms by which this binding fails, too. Positively-charged magnesium ions—which bind to the negatively-charged LPS—normally stabilize the cell membrane of these types of bacteria. When the concentration of magnesium is low, the bacteria have a system for masking the negative charges to keep the membrane stable. The cell has control systems that regulate this masking, only turning it on when necessary. A mutation can damage the control system, resulting in the masking system being turned on continually. The cell cannot turn it off. The reduction of the exposed negative charge then means that here, too, the antibiotic cannot bind to the cell and kill it. In this case, the mutated cell wastes resources when the system is not needed, so the bacteria survive less well in the absence of the antibiotic.
Any way you look at it, the mutations involved are breaking an existing function rather than creating a new mechanism involving new enzymes or proteins.
2. Restriction of the drug’s access to the target
Many antibiotics must be taken into the bacterium in order to kill it. An example is fosfomycin, which kills bacteria by blocking them from making a crucial component of the cell wall. There are different transport ‘pumps’ in the bacterial cell wall that move nutrients into the cell. Although these transporters are very selective in what they transport, fosfomycin is structurally like one of the usual nutrients they take up, and thus it hitches a ride into the cell.
Mutations in the genes that specify how the cell makes the transporters, or in regulator genes that stimulate their production, can result in no transporters, or less effective transporters. This means that no, or little, fosfomycin gets into the cell. Such cells are resistant to fosfomycin.
Once again, mutations wreck the normal function of the cell; they do not create new genes, new proteins, or enzymes. Far from being a ‘new improved model’, resistant cells also cannot take up the amounts of food substances that would normally enter via transporters that are now damaged or absent. Thus, in the absence of antibiotic, susceptible bacteria commonly out-compete resistant bacteria; so resistant ones comprise only a small percentage of the overall bacterial population.
Many species of bacteria have pumps that push things such as toxins out of the cell, called ‘efflux pumps’. These can also pump antibiotics out of the cell, thus stopping the antibiotic from killing the cell. Regulation of genes involved with the manufacture of efflux pumps is complex, but mutations in the regulators that limit the number of pumps can result in many more pumps being made, rendering the cell resistant to an antibiotic. This mode of resistance is particularly important for the fluoroquinolone class of antibiotics.5 Note also that with the broken regulatory system, the cells are wasting resources making excess pumps when they are not needed; thus, the mutant cells are less fit to survive in the absence of the antibiotic.
In each case here, mutations are ‘breaking’ genes for the pumps or the systems that regulate their production. This gives no support to mutations creating the new genes needed for evolution to proceed from bacteria to bacteriologists.
3. Inactivation of the antibiotic
Enzymes manufactured by a bacterium can break down (metabolize) an antibiotic. For example, enzymes called β-lactamases can break down penicillins. It might appear that a bacterium faced with an antibiotic and then acquiring such an ability would be a great example of evolution—a new enzyme; a new gene. However, in the instances known, the machinery to manufacture the antibiotic-destroying enzyme has never been observed to arise by mutation. So how did it come about?
It is now known that a bacterial cell can acquire the ability to break down an antibiotic from another bacterium that is already resistant.
Genes for such resistance can reside on small loops of DNA called plasmids that are external to the single circular bacterial chromosome. These plasmids can be transferred between different bacteria, even different species.6 One mechanism entails the connection of the bacterium with the resistance plasmid to one without it, via a tube (pilus).7 The resistant bacterium copies the plasmid and ‘donates’ a copy to the susceptible one (see diagram above).
Many plasmids contain multiple resistance genes for different types of antibiotics.
Again, with this class of resistance, no new genes are involved, but rather existing genes are transferred from a resistant type to a susceptible type.8
Breaking control systems
Resistance to penicillin provides a classic example. Some bacteria produce small amounts of penicillinase to break down the small amounts of naturally occurring penicillin in their environment, but not enough to cope with the amount given to patients. A mutation in the system that limits the amount of penicillinase produced can mean that far more is made, so the bacteria will be resistant. However, as with some of the other cases above, in the wild, these resistant bacteria, which can no longer control the production of penicillinase, will be out-competed by bacteria that are not squandering scarce resources on penicillinase production.
In all these cases, natural selection would favour the resistant strains where there is a lot of antibiotic present. However, while natural selection explains the survival of the resistance, it doesn’t explain the arrival of the resistance. Resistance results from modifying (usually breaking) an existing system, or transferring genes from those that already have it. Where a mutation breaks something, natural selection will tend to eliminate the resistant strains in the wild, yet favour them in an antibiotic-saturated environment.
Research into antibiotic resistance has revealed some good examples of mutations and natural selection that have helped the bacteria adapt to surviving antibiotics. However, none of the discoveries support the notion that accidental changes to existing genes/DNA (mutations) could generate the many thousands of new genes and gene networks needed to transform microbes into mankind, mangoes, and minke whales. Indeed, the changes studied underline just how limited mutations are in terms of ‘upward’ evolution.
References and notes
- Spellberg, B., The antibacterial pipeline: why it is drying up, and what must be done about it, In: Antibiotic Resistance: Implications for Global Health and Novel Intervention Strategies: Workshop Summary, National Academies Press, p. 327, 2011. Return to text.
- Cooper, M.A. and Shlaes, D., Fix the antibiotics pipeline, Nature 472(7341):32, 2011 | doi:10.1038/472032a. Return to text.
- Ling, L.L. et al., A new antibiotic kills pathogens without detectable resistance, Nature 517(7535):455–459, 2015 | doi:10.1038/nature14098; the antibiotic is called teixobactin. Return to text.
- Moffatt, J.H. et al., Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production, Antimicrob. Agents Chemother. 54(12):4971–7, 2010 | doi: 10.1128/AAC.00834-10. Return to text.
- Blair, J.M.A., Richmond, G.E., and Piddock, L.J.V., Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance (review), Future Microbiology 9(10):1165–1177, 2014; | doi:10.2217/fmb.14.66. Return to text.
- There are other ways that resistance genes can be transferred as well, involving bacteriophages (a virus that infects bacteria), transposons, and ‘naked DNA’. Return to text.
- This is called ‘conjugation’. Return to text.
- Evolutionists assume that these genes (for example, to make the penicillin-destroying enzyme β-lactamase) must have originally arisen by mutation, but that belief is not what is observed. Return to text.