Antibiotics and the Evolution of Antibiotic Resistance

Jose L Martinez, CNB Consejo Superior de Investigaciones Científicas, Madrid, Spain
Fernando Baquero, Department of Microbiology, Madrid, Spain

Published online: December 2009

DOI: 10.1002/9780470015902.a0021782

Antibiotics were introduced for human therapy few decades ago and their utilization has produced the rapid evolution of bacterial pathogens towards resistance. Before this recent and fast evolution, antibiotics and their resistance genes have evolved for millions of years in environmental microorganisms. Recent results suggest that, besides serving for inhibiting the growth of competitors, antibiotics might be signalling molecules in natural ecosystems and that some metabolic enzymes and signal-trafficking efflux pumps might render a phenotype of resistance in the presence of high concentrations of antibiotics. Antibiotic resistance can be developed by mutation or by the acquisition of resistance determinants by means of horizontal gene transfer. Spread of resistance is achieved through the combination of different elements, from resistance genes to plasmids and bacterial clones. The release of high amounts of antibiotics and resistance genes in natural habitats is challenging the microbial populations present in these ecosystems.

Key concepts

  • Some antibiotics can be involved in intermicrobial communication at the low concentrations likely found in most natural ecosystems.
  • The origin, spread and diversification of mechanisms of antibiotic resistance is an excellent model for studying real-time evolution.
  • The fact that a given gene confers resistance when transferred to a bacterial human pathogen does not necessarily mean that it plays the same functional role in its original host.
  • Exaptation is an evolutionary process by which a given determinant changes its function, without changing its structure, as the consequence of an environmental change.
  • Anthropogenic antibiotic pollution in the environment might modify the genetic structure of bacterial populations and communities.
  • Antibiotic resistance evolves frequently in a modular fashion, combining sequences, genes, genetic platforms and genetic vehicles.
  • The association of several antibiotic resistance genes in the same genetic vehicle favours their dissemination and persistence.
  • The spread of antibiotic resistance frequently occurs by the global dissemination of particularly transmissible bacterial resistant clones.
  • Antibiotic resistance is fixed in human or animal populations when the resistance genes enter into endemic clones.
  • Prediction of evolutionary trajectories should constitute the ultimate way to demonstrate the truth of hypothesis in evolutionary sciences.

Keywords: antibiotic resistance; horizontal gene transfer; bacterial evolution; bacterial ecology; environmental microbiology; mutation rate

Figure 1. Mechanisms of antibiotic resistance. Panel a, for inhibiting bacterial growth, an antibiotic (1), requires traverse the cellular envelopes either by specific transporters (2) or by diffusion through the membrane (3). In few occasions, the pre-antibiotic requires its activation by an intracellular enzyme (4). Finally, the antibiotic reaches its target at concentrations high enough to allow its inhibition (5). The presence of constitutively expressed efflux pumps (6) can decrease the intracellular concentration of the antibiotic and contributes to intrinsic resistance. Panel b, resistance can be achieved by changes that impede de entrance of the antibiotic in the cell (a, b), by enzymes that inactivate the antibiotic (c), by changes in the enzyme that activates the pre-antibiotic (d), by target modifications that impede the antibiotic interactions (e) or by overexpression of chromosomally encoded efflux pumps (f) or acquisition of these determinants by HGT, which reduces the intracellular concentration of the antibiotic.
Figure 2. The modular and hierarchical structure of the genetic elements involved in antibiotic resistance. The resistance gene contains domains that are critical for its function; at its turn, the resistance gene might be captured by an integron, and the integron can be inserted in a transposon, which is part of a plasmid, and the plasmid can be transferred to a particular bacterial lineage (clone), where genetic modular interactions between the chromosome and the plasmid might occur. Note that the spread of the resistance gene depends on the evolutionary success of each one of the genetic elements up in the hierarchy.
Figure 3. Integrons as gene-capture units. The integrons are composed by an integrase gene (int) and an arrangement of gene cassettes, which expression is driven by a strong promoter (p). Upstream the first gene cassettes the integrons contain a recombination site (attI) that mediates the integrase-driven recombination with the attC sites present in the gene cassettes.
Figure 4. Optimal genetic compositions of bacterial communities inside the hosts. Each white square represents an individual that is hosting an equilibrated array of different bacterial organisms (rainbow horizontal bar pattern, in the figure). This array can be perpetuated in the host by vertical transmission (mother–child, vertical column at the left) or by horizontal transmission to hosts sharing the same environment (upper section in the figure). Small variations in the bacterial organisms are permitted (eco-equivalent bacterial types still maintaining the rainbow pattern), as it is shown by different tones of green or violet, which might freely circulate among all ‘rainbow’ hosts. Eco-equivalent types are those that have the same or very similar function in the community of types. The introduction of these types originated from a similar community leads to the formation of near-to-the optimal mero-hybrid groups, that is, ensembles that have a part from a related group. If the genetic element containing the resistance gene (black circle) is located in a bacterium (or clone) that does not belong to the optimal array for this type of hosts (grey), it can be acquired by the host, but the probabilities of rejection are high (lower section of the figure). On the contrary, if the resistance gene is acquired by any of the members of the rainbow consortium, its possibilities of spreading and becoming endemic in these hosts are high. Large boxes represent the different ecosystems.
Figure 5. Evolutionary trajectories of antibiotic resistance as a hill-climbing process. Climbing gentle slopes might be required to have access to the high fitness (high levels of antibiotic resistance) peaks. In the yellow trajectory, such first step towards resistance might be limited for further developments, as it leads to a flat adaptive surface surrounded by lower fitness valleys (all possible mutations decrease resistance to the given antibiotic or to other antibiotic in the case of alternate selective challenges). Although the first event leading to resistance might occur later, in the blue trajectory, the flat adaptive surface reached after this first climbing event is larger, and resistance might spread and diversify without increasing the level of resistance (pale blue arrows). If second mutations are compatible with the first one, resistance can further increase (black arrow). In this black trajectory, the highest fitness peak is reached, but the surface on the top of the mountain is low and surrounded by steep cliffs, so that any genetic modification will reduce the fitness.
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Related Sub-Topics:

Adaptive Evolution | Molecular Evolution | Medical Microbiology | Microbial Evolution and Taxonomy
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Article Title: Antibiotics and the Evolution of Antibiotic Resistance
 
How to Cite close
Martinez, Jose L, and Baquero, Fernando(Dec 2009) Antibiotics and the Evolution of Antibiotic Resistance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021782]