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WIREs Syst Biol Med
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Adaptive resistance to antibiotics in bacteria: a systems biology perspective

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Despite all the major breakthroughs in antibiotic development and treatment procedures, there is still no long‐term solution to the bacterial antibiotic resistance problem. Among all the known types of resistance, adaptive resistance (AdR) is particularly inconvenient. This phenotype is known to emerge as a consequence of concentration gradients, as well as contact with subinhibitory concentrations of antibiotics, both known to occur in human patients and livestock. Moreover, AdR has been repeatedly correlated with the appearance of multidrug resistance, although the biological processes behind its emergence and evolution are not well understood. Epigenetic inheritance, population structure and heterogeneity, high mutation rates, gene amplification, efflux pumps, and biofilm formation have all been reported as possible explanations for its development. Nonetheless, these concepts taken independently have not been sufficient to prevent AdR’s fast emergence or to predict its low stability. New strains of resistant pathogens continue to appear, and none of the new approaches used to kill them (mixed antibiotics, sequential treatments, and efflux inhibitors) are completely efficient. With the advent of systems biology and its toolsets, integrative models that combine experimentally known features with computational simulations have significantly improved our understanding of the emergence and evolution of the adaptive‐resistant phenotype. Apart from outlining these findings, we propose that one of the main cornerstones of AdR in bacteria, is the conjunction of two types of mechanisms: one rapidly responding to transient environmental challenges but not very efficient, and another much more effective and specific, but developing on longer time scales. WIREs Syst Biol Med 2016, 8:253–267. doi: 10.1002/wsbm.1335 This article is categorized under: Analytical and Computational Methods > Computational Methods Physiology > Organismal Responses to Environment Biological Mechanisms > Regulatory Biology
Experimental setup for observing adaptive resistance. (a) Emergence of the resistance phenotype after successive and increasing antibiotic shocks. An isogenic population is subjected to a low concentration of antibiotic (down‐left plates). Although the population is genetically identical, enough phenotypic heterogeneity exists so that some cells are able to survive. These cells are allowed to duplicate until a reasonable population size is reached. Then a second and higher antibiotic shock is applied (middle plates). Again, some cells die whereas others are able to survive. This process is repeated several times (black dots), until populations able to survive near the dilution limit of some antibiotics are obtained (upper‐right plates). (b) Reversibility of the AdR phenotype after removal of the antibiotic. Resistant cells obtained by the previous description are transferred to an antibiotic‐free media. After some time, stability of the resistant phenotype is tested by subjecting the population to the same antibiotic concentration for which the population was previously resistant. As illustrated in the figure, the population is not able to withstand the same antibiotic concentration, suggesting that the resistant phenotype is unstable.
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Multidrug efflux pumps and their cost. Nonspecific efflux pumps (left protein) are known to export a wide range of substrates including antibiotics (purple circle) and metabolites (orange circle). Multidrug resistance systems (MDRS) such as the AcrAB‐TolC efflux pump regulatory network are known to increase the production of these efflux pumps in the presence of antibiotics. Additionally, they downregulate the production of porins (right protein), which allows the entrance of toxins. Thus, as efflux pumps can extrude important metabolites whereas porins allow the entrance of nutrients, cells with higher expression of the MDRS will have a clear fitness handicap: they will stop introducing important metabolites while pumping at the same time the ones left inside.
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Methylation patterns, epigenetic inheritance, and noise. In DNA mismatch repair, methylation can identify the parental strain after replication. Then methylation of the newly synthesized thread proceeds, and methyl groups are added using the parental strand as a template, replicating the same methylation pattern as the original double strand DNA (upper panel). Nonetheless, environmental stress and random fluctuations can make some of the methyl groups to be added at the wrong place (or not to be added at all) when methylation of the new strand takes place, changing permanently the methylation pattern of the daughter cells (bottom panel). As these methylation patterns are known to affect transcription rates, daughters may have similar but not equal gene expression patterns. This mechanism introduces correlated variability in gene expression in the population without changing the DNA sequence of nucleic acids.
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Continuous and discontinuous acquisition of resistance. It has been shown that genetic mutations usually step up the levels of resistance in a stepwise manner (red arrow), and that such resistance is usually stable against environmental changes (such as passing from an antibiotic rich media to an antibiotic‐free media, dotted line). It usually takes a long time to develop this stable form of resistance. Therefore, genetic variability has been showed to be unsuitable to explain the high survival rates observed when an isogenic population is confronted with low levels of antibiotic. Instead, gradual and faster, but unstable, mechanisms such as noise and inheritance of methylation patterns affecting gene expression have been proposed as an explanation for the rapid increase of adaptive resistance (blue arrow). We propose that these epigenetic mechanisms form part of the fast and transient mechanisms (FTM) response and that genetic mutations belong to the slow but stable mechanisms (SSM) response. The FTM allows the population to survive a temporal environmental pressure, and disappears once the environment returns to normal. But if the environmental pressure last for a long enough time, the right mutation appears and the SSM response comes in, increasing permanently the fitness of the population.
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Common situations for adaptive resistance to emerge. (a) It has been shown that antibiotic gradients promote rapid development of resistance. (b) Nutrient gradients induce different growth phases in bacterial populations, which are related to different levels of resistance. Scenarios such as biofilms, known to have low permeability, generate heterogeneous levels of resistance by establishing such nutrient gradients. This low permeability and gradient formation also applies for antibiotics. (c) Successive and increasing antibiotic shocks rapidly generate populations with high levels of resistance. (d) Contact with subinhibitory concentrations of antibiotic increases significantly the resistance of bacterial populations when later exposed to lethal concentrations.
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Physiology > Organismal Responses to Environment
Biological Mechanisms > Regulatory Biology
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