Bacterial evolution of antibiotic hypersensitivity

Lázár, Viktória; Palsson, Bernhard; Spohn, Réka; Nagy, István; Horváth, Balázs; Hrtyan, Mónika; Busa-Fekete, Róbert; Bogos, Balázs; Méhi, Orsolya; Csörgő, Bálint; Pósfai, György; Fekete, G.; Szappanos, Balázs; Kégl, Balázs; Papp, Balázs; Pál, Csaba

doi:10.1038/msb.2013.57

Cited by 308 publications

(407 citation statements)

References 48 publications

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“…This could have important clinical consequences, as unsuccessful antibiotic treatments might select for cross-tolerance and limit the efficacy of subsequent treatments with other antibiotics. It is also interesting to note how our observations differ from the results of recent work on the experimental evolution of aminoglycoside resistance (55). In this work, researchers describe how increased aminoglycoside resistance correlates with enhanced susceptibility to a whole range of other antibiotics, including ciprofloxacin, vancomycin, and ␤-lactams.…”

Section: Figcontrasting

confidence: 68%

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Michiels

Bergh

Verstraeten

et al. 2016

Antimicrob Agents Chemother

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bHealth care-associated infections present a major threat to modern medical care. Six worrisome nosocomial pathogens-Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.-are collectively referred to as the "ESKAPE bugs." They are notorious for extensive multidrug resistance, yet persistence, or the phenotypic tolerance displayed by a variant subpopulation, remains underappreciated in these pathogens. Importantly, persistence can prevent eradication of antibiotic-sensitive bacterial populations and is thought to act as a catalyst for the development of genetic resistance. Concentration-and time-dependent aminoglycoside killing experiments were used to investigate persistence in the ESKAPE pathogens. Additionally, a recently developed method for the experimental evolution of persistence was employed to investigate adaptation to high-dose, extended-interval aminoglycoside therapy in vitro. We show that ESKAPE pathogens exhibit biphasic killing kinetics, indicative of persister formation. In vitro cycling between aminoglycoside killing and persister cell regrowth, evocative of clinical high-dose extended-interval therapy, caused a 37-to 213-fold increase in persistence without the emergence of resistance. Increased persistence also manifested in biofilms and provided cross-tolerance to different clinically important antibiotics. Together, our results highlight a possible drawback of intermittent, high-dose antibiotic therapy and suggest that clinical diagnostics might benefit from taking into account persistence.

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Section: Figcontrasting

confidence: 68%

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Michiels

Bergh

Verstraeten

et al. 2016

Antimicrob Agents Chemother

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“…Bacterial growth was monitored by measuring the optical density (OD 600 ) of the liquid cultures at a single time point. Preliminary experiments showed that a single reading of optical density after 18 h of incubation showed strong linear correlation with the area under the growth curve (a descriptor of overall inhibitory effect that covers the entire growth period) (21). Briefly, this was determined using parallel cultures of E. coli grown in ten 384-well microtiter plates under previously stated conditions.…”

Section: Methodsmentioning

confidence: 99%

Antagonism between Bacteriostatic and Bactericidal Antibiotics Is Prevalent

Ocampo

Lázár

Papp

et al. 2014

Antimicrob Agents Chemother

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235

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f Combination therapy is rarely used to counter the evolution of resistance in bacterial infections. Expansion of the use of combination therapy requires knowledge of how drugs interact at inhibitory concentrations. More than 50 years ago, it was noted that, if bactericidal drugs are most potent with actively dividing cells, then the inhibition of growth induced by a bacteriostatic drug should result in an overall reduction of efficacy when the drug is used in combination with a bactericidal drug. Our goal here was to investigate this hypothesis systematically. We first constructed time-kill curves using five different antibiotics at clinically relevant concentrations, and we observed antagonism between bactericidal and bacteriostatic drugs. We extended our investigation by performing a screen of pairwise combinations of 21 different antibiotics at subinhibitory concentrations, and we found that strong antagonistic interactions were enriched significantly among combinations of bacteriostatic and bactericidal drugs. Finally, since our hypothesis relies on phenotypic effects produced by different drug classes, we recreated these experiments in a microfluidic device and performed time-lapse microscopy to directly observe and quantify the growth and division of individual cells with controlled antibiotic concentrations. While our single-cell observations supported the antagonism between bacteriostatic and bactericidal drugs, they revealed an unexpected variety of cellular responses to antagonistic drug combinations, suggesting that multiple mechanisms underlie the interactions.

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“…The most Drug sequence influences evolution of resistance commonly mutated gene was fusA1, which encodes elongation factor G and was mutated in 11 different replicate lineages adapted to tobramycin. fusA1 has been observed to be mutated in clinical isolates of P. aeruginosa [39][40][41], as well as in adaptive evolution studies to aminoglycosides in P. aeruginosa [34] and E. coli [12,16,18]. Mutations in fusA1 may also contribute to altered intracellular (p)ppGpp levels, which may modulate virulence in P. aeruginosa [41].…”

Section: Genomic Mutations Of Adapted Lineagesmentioning

confidence: 99%

“…Recent studies have explored how adaptation to an antibiotic can cause bacteria to concurrently become more susceptible or more resistant to other drugs, an effect termed collateral sensitivity or collateral resistance [14,16,17]. Collateral sensitivities between drugs have been used to design drug cycling strategies and to explain the decreased rate of adaptation to certain antibiotics [12,14,[18][19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

History of Antibiotic Adaptation Influences Microbial Evolutionary Dynamics During Subsequent Treatment

Yen

Papin

2016

Preprint

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Antibiotic regimens often include the sequential changing of drugs to limit the development and evolution of resistance of bacterial pathogens. It remains unclear how history of adaptation to one antibiotic can influence the resistance profiles when bacteria subsequently adapt to a different antibiotic. Here, we experimentally evolved Pseudomonas aeruginosa to six 2-drug sequences. We observed drug order-specific effects, whereby adaptation to the first drug can limit the rate of subsequent adaptation to the second drug, adaptation to the second drug can restore susceptibility to the first drug, or final resistance levels depend on the order of the 2-drug sequence. These findings demonstrate how resistance not only depends on the current drug regimen but also the history of past regimens. These orderspecific effects may allow for rational forecasting of the evolutionary dynamics of bacteria given knowledge of past adaptations and provide support for the need to consider the history of past drug exposure when designing strategies to mitigate resistance and combat bacterial infections. Author summaryBacteria readily adapt to their environments and can develop ways to survive and grow in the presence of antibiotics. While many studies have investigated how bacteria evolve to become resistant to single drugs, it is unclear how adaptation to other drugs and environments in the past affect the way bacteria adapt to new drugs and environments. In this study, we allowed bacteria in a laboratory setting to adapt to three different antibiotics. We first exposed wild-type susceptible bacteria to high concentrations of the three antibiotics individually and then exposed these populations to each of the other drugs. By tracking the levels of resistance to all three drugs in all of the treatments, we identified cases in which past adaptation to one treatment influenced subsequent evolutionary dynamics with regard to both phenotypes (levels of resistance) and genotypes (genes that became mutated). Additionally, by allowing bacterial isolates originating from human patients to adapt to the three drugs, we recapitulated a subset of the adaptation history-dependent evolutionary dynamics. Overall, this study sheds light on how adaptation history in PLOS Biology | https://doi.org/10.1371/journal

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Bacterial evolution of antibiotic hypersensitivity

Cited by 308 publications

References 48 publications

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

In Vitro Emergence of High Persistence upon Periodic Aminoglycoside Challenge in the ESKAPE Pathogens

Antagonism between Bacteriostatic and Bactericidal Antibiotics Is Prevalent

History of Antibiotic Adaptation Influences Microbial Evolutionary Dynamics During Subsequent Treatment

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