Antibiotic resistance: turning evolutionary principles into clinical reality

Andersson, Dan I.; Balaban, Nathalie Q.; Baquero, Fernando; Courvalin, Patrice; Glaser, Philippe; Gophna, Uri; Kishony, Roy; Molin, Søren; Tønjum, Tone

doi:10.1093/femsre/fuaa001

Cited by 186 publications

(131 citation statements)

References 198 publications

(145 reference statements)

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“…We found that treatments concentrations ~2x MIC 0 produced the most resistant populations ( Figure 2C). The selective pressures of sub-inhibitory antibiotic concentrations have often been considered high-risk for the evolution of resistance (14,38). Yet, our results indicated that concentrations near or just above MIC 0 lead to the highest resistance levels in these conditions.…”

mentioning

confidence: 54%

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Langevin

Meouche

Dunlop

2020

Preprint

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ABSTRACTAntibiotic resistance has become a major public health concern as bacteria evolve to evade drugs, leading to recurring infections and a decrease in antibiotic efficacy. Systematic efforts have revealed mechanisms involved in resistance; yet, in many cases, how these specific mechanisms accelerate or slow the evolution of resistance remains unclear. Here, we conducted a systematic study of the impact of the AcrAB-TolC efflux pump and its expression on the evolution of antibiotic resistance. We mapped how population growth rate and resistance change over time as a function of both the antibiotic concentration and the parent strain’s genetic background. We compared strains lacking functional AcrAB-TolC efflux pumps, the wild type strain, and those overexpressing the pumps. In all cases, resistance emerged when cultures were treated with chloramphenicol concentrations near the MIC of the parent strain. Strains grown in concentrations just above the MIC were the most prone to evolving high levels of drug resistance, in some cases reaching values that far exceed the concentrations they were treated with. The genetic background of the parent strain also influenced resistance acquisition. The strain overexpressing pumps evolved resistance more slowly and at lower levels than the wild type strain or the strain lacking functional pumps. In contrast, the wild type strain rapidly achieved resistance through mutations in pump genes and their associated regulators. Overall, our results suggest that treatment conditions just above the MIC pose the largest risk for the evolution of resistance, and precise control of pump expression levels accelerates this process.IMPORTANCECombatting the rise of antibiotic resistance is a significant challenge. Efflux pumps are an important contributor to drug resistance, and they exist across many cell types and can export numerous classes of antibiotics. Cells with efflux pumps can regulate pump expression to maintain low intracellular drug concentrations. Here, we explored a three-dimensional evolutionary landscape, in which we mapped how resistance emerged depending on the antibiotic concentration, the presence of efflux pumps and their regulators, and time. We found that treatments just above the antibiotic concentration that inhibits growth of the parent strain were most likely to promote resistance, but that efflux pump levels influence the severity of these outcomes. These results indicate that there are specific treatment regimens and strain backgrounds that are especially problematic for the evolution of resistance.

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mentioning

confidence: 54%

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Langevin

Meouche

Dunlop

2020

Preprint

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“…5d) and this phenomenon was also observed in lineages evolved with tobramycin alone. Thus, treatment with a combination of bactericidal antibiotics strongly favors the development of multidrug tolerant P. aeruginosa 2 . The observation that some of the tolerant lineages acquired intermediate-level resistance against both drugs at later time points (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The great therapeutic achievements of antibiotics have been dramatically undercut by the steady evolution of survival strategies allowing bacteria to overcome antibiotic action 1,2 . Although resistance plays a major role in antibiotic-treatment failure, bacteria can use resilience mechanisms such as tolerance to survive antibiotic treatment 3 .…”

Section: Introductionmentioning

confidence: 99%

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Santi

Manfredi²,

Maffei³

et al. 2020

Preprint

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The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed in-patient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.

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“…Finally, antibiotic options are often highly constrained by the patient’s clinical situation and the availability of culture data. There is often uncertainty about the microbial composition of the infection, and published data guiding the decision-making process in such cases have been incomplete [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Why is preventing antibiotic resistance so hard? Analysis of failed resistance management

Zhou

Barbosa

Woods

2020

Evolution, Medicine, and Public Health

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Abstract We describe the case of a patient with pancreatitis followed by intra-abdominal infection in which source control was not achieved. Antimicrobial therapy led to the emergence of resistance in multiple organisms through multiple population dynamics processes. While the initial insult was not due to infection, subsequent infections with resistant organisms contributed to a poor outcome for the patient. Though resistance evolution was a known risk, it was difficult to predict the next organism that would arise in the setting of antibiotic pressure and its resistance profile. This case illustrates the clinical challenge of antibiotic resistance that current approaches cannot readily prevent. Lay summary Why is antibiotic resistance management so complex? Distinct evolutionary processes unfold when antibiotic treatment is initiated that lead, separately and together, to the undesired outcome of antibiotic resistance. This clinical case exemplifies some of those processes and highlights the dire need for evolutionary risk assessments to be incorporated into clinical decision making.

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Antibiotic resistance: turning evolutionary principles into clinical reality

Cited by 186 publications

References 198 publications

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Mapping the Role of AcrAB-TolC Efflux Pumps in the Evolution of Antibiotic Resistance Reveals Near-MIC Treatments Facilitate Resistance Acquisition

Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Why is preventing antibiotic resistance so hard? Analysis of failed resistance management

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