Acceleration of Emergence of Bacterial Antibiotic Resistance in Connected Microenvironments

Zhang, Qiucen; Lambert, Guillaume; Liao, David; Kim, Hyunsung; Robin, Kristelle; Tung, Chih-kuan; Pourmand, Nader; Austin, Robert H.

doi:10.1126/science.1208747

Cited by 495 publications

(499 citation statements)

References 23 publications

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“…It has been shown that even when bacteria was exposed to 200 times its minimum inhibitory concentration (MIC), it can develop resistance within 10 hours [57]. This suggests that our previous understanding that bacterial resistance is directly related to being exposed to below-MIC concentrations of antibiotics [58] may be incomplete.…”

Section: Discussionmentioning

confidence: 99%

A fully functional drug-eluting joint implant

et al. 2017

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Despite advances in orthopedic materials, the development of drug-eluting bone and joint implants that can sustain the delivery of the drug and maintain the necessary mechanical strength in order to withstand loading has remained elusive. Here, we demonstrate that modifying the eccentricity of drug clusters and the percolation threshold in ultrahigh molecular weight polyethylene (UHMWPE) results in maximized drug elution and in the retention of mechanical strength. The optimized UHMWPE eluted antibiotic at a higher concentration for longer than the clinical gold standard antibiotic-eluting bone cement while retaining the mechanical and wear properties of clinically used UHMWPE joint prostheses. Treatment of lapine knees infected with Staphylococcus aureus with the antibiotic-eluting UHMWPE led to complete bacterial eradication and to the absence of detectable systemic effects. We argue that the antibiotic-eluting UHMWPE joint implant is a promising candidate for clinical trials.

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Section: Discussionmentioning

confidence: 99%

A fully functional drug-eluting joint implant

et al. 2017

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“…Glucose gradient or chemotherapy gradients have been used to study the phenotypic progression of cancer in complex environments (4,5); now we add the compartmentalization of small, possibly clonal, communities within the gradient. Just as rapid fixation of drug-resistant bacterial mutants in a metapopulation can occur in an environment with drug gradients and connected microhabitats (6)(7)(8), we demonstrate that an ecologically designed microenvironment, with drug gradients and connected microhabitats, can drive the rapid emergence of resistance in MM. We then use transcriptome sequencing of the far more complex (than in bacteria) genomic substitution patterns in the evolved MM cancer cells to address the question: What is the role of both substitutions and nonsubstitutions in the evolved genomes of the resistant cells in driving drug resistance?…”

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confidence: 99%

Ancient hot and cold genes and chemotherapy resistance emergence

Zhang

Lambert

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.cancer | emergence | ancient genes | cold | hot

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“…Examples include viral adaptation during infection (1), the emergence of antibiotic resistance (2), artificial selection in biotechnology (3), and cancer (4). Rapid adaptation is characterized by three key features: (i) the availability of strongly advantageous traits accessible by rare mutations, (ii) an elevated mutation rate (1), and (iii) a dynamic population size (5).…”

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confidence: 99%

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

McFarland

Mirny

Korolev

2014

Proc. Natl. Acad. Sci. U.S.A.

149

187

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Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations-a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies.

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Acceleration of Emergence of Bacterial Antibiotic Resistance in Connected Microenvironments

Cited by 495 publications

References 23 publications

A fully functional drug-eluting joint implant

A fully functional drug-eluting joint implant

Ancient hot and cold genes and chemotherapy resistance emergence

Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

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