Abstract:

Antibiotic resistance represents the highest likelihood threat towards human civilisation as we know it. The mechanism by which antibacterial resistance arises is through natural section and evolution of bacterial strains that have acquired a suite of advantageous mutations, allowing them to circumvent the action of antibacterial drugs. However, these mutations typically have pleiotropic effects – genetic correlation such that one gene has an effect on multiple traits – which hinder the activity of alternative fitness components, such as growth rate. This phenomenon has been thought to maintain a low frequency of antibiotic resistant strains of bacteria within the population, but recent evidence has suggested the possibility of beneficial pleiotropy, which would alarmingly encourage the spread of these strains. This article highlights the dire need for us to form a resistance against antibacterial resistant ‘Superbugs’.

Main Text:

Stop and take a moment to quickly sweep your mind over the history of life on Earth; all 3.8 billion years. Now zoom in on the current human civilisation. We live in a rapidly changing time that strongly contrasts the gradual evolutionary establishment of the Earth’s vast biodiversity. Every day, we are irrevocably shaping the future course of history.

“Humans must populate a new planet within 100 years if we are to survive”[1].

It sounds drastic, but when the dire prediction comes from none other than Steven Hawkins, the world must listen. However, the question remains, what imminent threats are contributing to these bold claims? The Doomsday Clock currently stands at 2 minutes to midnight[2], citing the growing tensions of a global nuclear catastrophe and the nigh inexorable effects of climate change. Despite these threats, Darling and Schulze-Makuch write in Megacatastrophes that nothing is as likely as the emergence of a global pandemic reminiscent of the plague, qualitatively estimated at a probability of 7.5/10[3]. But haven’t we vastly improved our medical weaponry since the bubonic plague of the 14th Century? Shouldn’t we be moving towards an increase in life expectancy, rather than in the opposite direction with a severe magnitude? Counterintuitively, the advancement of modern medicine has produced an unforeseen threat for human health; the emergence of multiple drug resistant (MDR) microbes[4].

The use of antibiotics for the treatment of bacterial infections applies a strong selective pressure on the population, typically wiping them out but offering an extremely advantageous benefit for strains that generate a mutational safeguard against the drug’s effect. The extent of the threat is due to:

  • The dwindling number of antibacterial agents that effectively perform their intended action
  • The increasingly interconnected global community that elevates the potential rate of transmission of a future pandemic
  • The lack of novel antibacterial agents currently being developed in the pharmaceutical pipeline due to the lack of economic incentive[5].

An exhibition of the rate at which bacteria are able to evolve, spurring on potentially lethal antibacterial resistance, was shown during a ‘Natural Selection’ practical for the undergraduate evolution course Biol2201.  The bacteria B. thuringiensis was initially plated on multiple agar plates: A regular plate, a plate gradated with the antibiotic streptomycin from high to low concentration, and a plate with a uniformly high streptomycin concentration. Bacteria that grew at the highest point along the streptomycin concentration gradient were selected as having developed the highest partial antibiotic resistance. After 1 week, this colony was re-streaked on a standard agar plate to assess their relative growth under antibacterial-free conditions.

The most striking result, besides the fast rate that bacteria are capable of evolving, was a consistently lower capacity for growth for the partial antibacterial resistant strains in the absence of streptomycin, as shown in Figure 1. This phenomenon can be explained by antagonistic pleiotropy. When gaining antibiotic resistance, an associated fitness cost involving growth rate is incurred.

Antibiotic Resistance 2

Figure 1: Results of antibiotic resistance selection experiment. Growth was assessed qualitatively on a scale of 1-4, relative to the growth of the bacteria in the absence of Streptomycin (4).                                                                                                                                                                                           Initial conditions display the growth of non-resistant strains of B. thuringiensis on agar plate without streptomycin (control) and with streptomycin (strep). Final conditions show the growth of the selected partially-resistant strains on ‘control’ and ‘strep’ plates.

Mutations that confer antibiotic resistance are typically concentrated highly conserved regions known as ‘housekeeping genes’[6]. These mutations usually result in a decrease in fitness associated with fundamental cellular activities such as growth and metabolism. However, a recent study has shown that while mutations within housekeeping genes typically have antagonistic effects on fitness, there is evidence for additional beneficial adaptive effects outside of antibacterial resistance. This is important, because previous beliefs were that decreased fitness effects associated with antagonistic pleiotropy would lead to diminishing numbers of these strains once the antimicrobial pressure was lifted. However, these results would indicate that resistant strains could accumulate in the population[7].

Removing a layer of abstraction from this study, an analogous example for the phenomenon of antagonistic pleiotropy within human evolution comes in the form of Crohn’s Disease. Just as bacteria need to evolve resistance to antimicrobial drugs, Eukaryotic organisms need to evolve against the attack of bacteria themselves. A suite of alleles (specific point within a gene where there are differences in the DNA code throughout the population) in humans have combined to individually confer a slight immunological-related fitness advantage against a host of bacterial threats, leading to their increase in frequency in the population. However, said alleles have also antagonistically been implicated in the pathophysiology of Crohn’s disease, which is a immune system disease contributed towards by many alleles of small effects. The lack of the removal of these alleles is due to the fact that the reduction in relative reproductive fitness of Crohn’s disease sufferers is insignificant compared to the benefits obtained against infectious agents.

These finding highlight the dire need for research into limiting and combating antibiotic resistance. This includes the development of antibiotic agents that have low selective pressure on microbes, which inhibit the effect of infection but still allow for reproduction, so as to prevent adaption. In addition, we need to develop ‘smart’ antibiotics that selectively target pathogenic bacteria, but leave beneficial host microflora unaffected[7].

The future is in, and on, our hands!


Sources:

  1. BBC. BBC and partners launch year of science and technology. 2017; Available from: http://www.bbc.co.uk/mediacentre/mediapacks/tomorrows-world/television.
  2. Bulletin of the Atomic Scientist. Doomsday Clock Timeline. 2017; Available from: http://thebulletin.org/timeline.
  3. Darling, D. and D. Schulze-Makuch, Megacatastrophes! : Nine Strange Ways the World Could End. 2012: Oneworld Publications.
  4. Levy, S.B., The Challenge of Antibiotic Resistance. Scientific American, 1998. 278(3): p. 46-53.
  5. Sukkar, E., Why are there so few antibiotics in the research and development pipeline? The Pharmaceutical Journal, 2013. 291: p. 250.
  6. Scholar, E.M. and W.B. Pratt, The Antimicrobial Drugs. Vol. 2. 2000: Oxford University Press.
  7. Hershberg, R., Antibiotic-Independent Adaptive Effects of Antibiotic Resistance Mutations. Trends in Genetics, 2017. 33(8): p. 521-528.
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Resisting ‘Superbugs’ in the Post-antibiotic Era

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