The genetic underground of antibiotic resistance

doi:10.1126/science.abf7922

GSTDTAP > 气候变化

DOI	10.1126/science.abf7922
	The genetic underground of antibiotic resistance
	Mattia Zampieri
	2021-02-19
发表期刊	Science
出版年	2021
英文摘要	Metabolism has mostly been studied for its role in providing building blocks and energy to sustain cell duplication. Previously unexplored roles of metabolism in signaling and regulation have now been unveiled. Mounting evidence suggests a fundamental role of microbial metabolism in mediating the short-term ([ 1 ][1], [ 2 ][2]) and long-term responses to antimicrobial agents ([ 3 ][3]), opening possibilities for combination therapies that could hamper the evolution of antibiotic resistance ([ 4 ][4]–[ 6 ][5]). Given their impact on bacterial growth, indirect effects of antibiotic treatment on metabolism were to be expected. But there are also common and drug-specific metabolic changes that are independent from growth inhibition and can play an important role in antibiotic lethality ([ 1 ][1], [ 5 ][6], [ 6 ][5]). If metabolism plays a key role in mediating antibiotic response and drug toxicity, does metabolism have a role in antibiotic resistance? On page 799 of this issue, Lopatkin et al. ([ 7 ][7]) reveal the interplay between metabolism and antibiotic resistance in clinically relevant pathogens. By analyzing a library of 7243 Escherichia coli genomes, Lopatkin et al. observed that in clinical strains isolated from human patients, mutations that map to core metabolic functions were as frequent as well-known resistance mutations ([ 8 ][8]), such as those affecting the drug target. However, the authors showed that these metabolic mutations are observed significantly less frequently in traditional in vitro evolution experiments that select for antibiotic resistance. Because a mutation conferring antibiotic resistance may exhibit different fitness costs depending on the environmental conditions, evolutionary trajectories to antibiotic resistance can be influenced by the nutritional compositions of the environment and treatment regimens ([ 2 ][2]–[ 4 ][4]). Additionally, the sequence of solutions adopted to evolve antibiotic resistance can be radically different if bacteria are continuously exposed to a high dosage of the antibiotic or if selection is applied by intermittent antibiotic exposure ([ 2 ][2]). Therefore, Lopatkin et al. asked whether, in contrast to classical approaches that rely on growth-dependent selection, in vitro evolution protocols that maximize metabolic adaptation may be more representative of genetic selection for antibiotic resistance in vivo. ![Figure][9] Metabolic protection from antibiotics Genetic diversity in antibiotic-resistant populations of Escherichia coli result from convergent paths to antibiotic resistance. These paths also involve various mutations in metabolic genes that can fulfill a common task: shielding bacterial metabolism from the effects of antibiotic treatment. GRAPHIC: V. ALTOUNIAN/ SCIENCE Lopatkin et al. first used a traditional protocol for evolution of antibiotic-resistant E. coli : serial passages of populations continuously challenged with an increasing concentration of three representative bactericidal drugs that target protein synthesis (streptomycin), DNA replication (ciprofloxacin), and cell wall biosynthesis (carbenicillin). They found larger genetic variability by sequencing entire populations versus isolated clones, emphasizing how clonal analysis can mask the role of relatively infrequent, but potentially equally relevant, mutations. Many of the high-frequency mutations were consistent with classical resistance mechanisms ([ 8 ][8]), such as mutations in drug targets or regulators of multidrug response genes. Notably, although at low frequency, many more mutations in metabolic genes were found at the population level than at the clonal level, suggesting that an underlying diverse genetic network of mutations directly impinging on metabolism could play a more important role than previously anticipated in mediating the evolution of resistance to antibiotics. Lopatkin et al. suspected that in classical experimental evolution, constant exposure to antibiotics creates a strong selective pressure for growth-related processes and possibly masks the importance of mutated metabolic genes in conferring protection from antibiotic-induced stress. To test whether frequency of metabolic mutations throughout the evolution of antibiotic resistance could be increased, the authors cycled E. coli cells between 1 hour of antibiotic treatment per day and 22 hours of growth without antibiotics. Metabolic activity during treatment was modulated by increasing the temperature 1°C higher every day for 10 days, starting at 20°C (low metabolic activity). As a result of this new protocol, metabolic mutations now dominated the genetic changes in the emerging strains. Moreover, metabolic mutations were not just a consequence of the cycling between growing and nongrowing conditions but were exclusively associated with exposure to antibiotics. The same metabolic mutations were found to be common between strains resistant to different antibiotics, reflecting the potential relevance of modulating metabolism as a general adaptive strategy against antibiotic-mediated stress. These findings raised the question of whether metabolic mutations are necessary to facilitate evolution of resistance ([ 2 ][2]) and/or sufficient to acquire antibiotic resistance. Lopatkin et al. showed that on average, metabolic mutations alone can confer mild, but measurable, antibiotic resistance, suggesting that increased survival is unlikely a result of increased tolerance—that is, the ability to survive antibiotic exposure for a longer time. For example, although in wild-type E. coli carbenicillin induced a strong up-regulation of enzymes in the tricarboxylic acid cycle—which is responsible for converting organic fuel molecules (e.g., glucose) and oxygen into carbon dioxide, water, and energy—a mutation in one of these enzymes, the 2-oxoglutarate dehydrogenase enzyme ( sucA ), is sufficient to not only abolish this up-regulation but also confer carbenicillin resistance. These findings reinforce that antibiotic efficacy is intimately linked to the cell's metabolic state. These analyses suggest that rewiring of central metabolism may be a general strategy to acquire antibiotic resistance, but the scope of metabolic changes resulting from these mutations remains to be systematically unraveled. One hypothesis emerging from this study is that different metabolic mutations can converge to similar adaptive changes and provide resistance to antibiotics with largely different modes of action. Hence, although individually at lower frequency than classical resistance mutations, it is possible that different metabolic mutations can play the same role in mediating antibiotic resistance (see the figure). Advances in technologies that enable the monitoring of dynamic metabolic changes in response to genetic and environmental perturbations combined with computational models of cellular metabolism will help researchers to investigate the common scope of diverse metabolic mutations in antibiotic resistance ([ 3 ][3], [ 5 ][6], [ 9 ][10], [ 10 ][11]). Predicting how mutations affect the metabolic state of cells, alter drug action, and ultimately shape the fitness landscape of resistance mutations will be of paramount importance to leverage this understanding in the optimization of treatment regimens and the discovery of new drugs and combination therapies. Small molecules that interfere with respiratory and fermentative metabolism might improve the killing efficacy of classical antibiotics ([ 4 ][4], [ 11 ][12]) and hamper the evolution of resistance by changing the fitness landscape of antibiotic resistance ([ 3 ][3], [ 5 ][6], [ 6 ][5]). From the data and analysis presented by Lopatkin et al. , mechanisms by which pathogenic bacteria can become resistant in vivo can be unraveled. 1. [↵][13]1. P. Belenky et al ., Cell Rep. 13, 968 (2015). [OpenUrl][14][CrossRef][15][PubMed][16] 2. [↵][17]1. O. Fridman, 2. A. Goldberg, 3. I. Ronin, 4. N. Shoresh, 5. N. Q. Balaban , Nature 513, 418 (2014). 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/315715
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Mattia Zampieri. The genetic underground of antibiotic resistance[J]. Science,2021.
APA	Mattia Zampieri.(2021).The genetic underground of antibiotic resistance.Science.
MLA	Mattia Zampieri."The genetic underground of antibiotic resistance".Science (2021).