Minimizing treatment-induced emergence of antibiotic resistance in bacterial infections

Stracy, Mathew; Snitser, Olga; Yelin, Idan; Amer, Yara; Parizade, Miriam; Katz, Rachel; Rimler, Galit; Wolf, Tamar; Herzel, Esma; Koren, Gideon; Kuint, Jacob; Foxman, Betsy; Chodick, Gabriel; Shalev, Varda; Kishony, Roy

doi:10.1126/science.abg9868

Cited by 156 publications

(91 citation statements)

References 37 publications

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“…The second issue is the importance of considering the preexisting genetic diversity in bacterial communities when assessing the potential for AMR evolution. Our results from patient JWC, together with findings from other recent studies 24,29,30 , show that genetic diversity fuels AMR evolution. Most research to date on within- patient evolution of AMR (including this study) has failed properly to screen for community diversity.…”

Section: Discussionsupporting

confidence: 86%

Within-patient evolution of plasmid-mediated antimicrobial resistance

DelaFuente

Toribio-Celestino

Santos-López

et al. 2022

Preprint

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Antibiotic resistance (AMR) in bacteria is a major threat to public health, and one of the key elements in the spread and evolution of AMR in clinical pathogens is the transfer of conjugative plasmids. The drivers of AMR evolution have been extensively studied in vitro, but the evolution of plasmid-mediated AMR in vivo remains poorly explored. Here, we tracked the evolution of the clinically-relevant plasmid pOXA-48, which confers resistance to the last-resort antibiotics carbapenems, in a large collection of enterobacterial clones isolated from the gut of hospitalised patients. Combining genomic and experimental approaches, we first characterized plasmid diversity and the genotypic and phenotypic effects of multiple plasmid mutations on a common genetic background. Second, using cutting-edge genomic editing in wild-type multidrug resistant enterobacteria, we dissected three cases of within-patient plasmid-mediated AMR evolution. Our results revealed, for the first time, compensatory evolution of plasmid-associated fitness cost, as well as the evolution of enhanced plasmid-mediated AMR, in bacteria evolving within the gut of hospitalised patients. Crucially, we observed that the evolution of plasmid-mediated AMR in vivo involves a pivotal trade-off between resistance levels and bacterial fitness. This study highlights the need to develop new evolution-informed approaches to tackle plasmid-mediated AMR dissemination.

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Section: Discussionsupporting

confidence: 86%

Within-patient evolution of plasmid-mediated antimicrobial resistance

DelaFuente

Toribio-Celestino

Santos-López

et al. 2022

Preprint

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“…Emergence of antimicrobial resistance in patients can also be predicted based on their past treatment history, clinical risk factors, and past colonization by resistant isolates. 112 Future work may rely further upon predictions of patient risks for resistant infections using metagenomics of the human microbiome. Taken together, the use of new methodology can aid in developing more nuanced models of the resistome, moving the field from descriptors of the presence of ARGs toward an improved understanding of the risks and clinical relevance of ARG abundance and transmission in the human microbiome.…”

Section: Next-generation Approaches To Detect and Predict Arg Transmi...mentioning

confidence: 99%

Good microbes, bad genes? The dissemination of antimicrobial resistance in the human microbiome

et al. 2022

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A global rise in antimicrobial resistance among pathogenic bacteria has proved to be a major public health threat, with the rate of multidrug-resistant bacterial infections increasing over time. The gut microbiome has been studied as a reservoir of antibiotic resistance genes (ARGs) that can be transferred to bacterial pathogens via horizontal gene transfer (HGT) of conjugative plasmids and mobile genetic elements (the gut resistome). Advances in metagenomic sequencing have facilitated the identification of resistome modulators, including live microbial therapeutics such as probiotics and fecal microbiome transplantation that can either expand or reduce the abundances of ARG-carrying bacteria in the gut. While many different gut microbes encode for ARGs, they are not uniformly distributed across, or transmitted by, various members of the microbiome, and not all are of equal clinical relevance. Both experimental and theoretical approaches in microbial ecology have been applied to understand differing frequencies of ARG horizontal transfer between commensal microbes as well as between commensals and pathogens. In this commentary, we assess the evidence for the role of commensal gut microbes in encoding antimicrobial resistance genes, the degree to which they are shared both with other commensals and with pathogens, and the host and environmental factors that can impact resistome dynamics. We further discuss novel sequencing-based approaches for identifying ARGs and predicting future transfer events of clinically relevant ARGs from commensals to pathogens.

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“…The literatures reported that the re‐establishment of those bacterial defense systems required a long‐term evolution brought by clinically dedicated AbR genes. [ 53,54 ] In contrast, our MWH treatment on MDR E. coli bacteria only lasted for 10 min. Therefore, we speculated that the genetic evolution of MDR E. coli bacteria would unlikely develop any new AbR in such short period of time.…”

Section: Discussionmentioning

confidence: 99%

Reversing Multidrug‐Resistant Escherichia coli by Compromising Its BAM Biogenesis and Enzymatic Catalysis through Microwave Hyperthermia Therapy

Mao

Jin

Xiang

et al. 2022

Adv Funct Materials

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Multidrug‐resistant (MDR) bacteria are emerging and disseminating rapidly, undoubtedly posing an urgent threat to global public health. One particular concern is that MDR Gram‐negative bacteria are immunized to available antibiotics owing to a series of biogenetic effects, including the β‐barrel assembly machine (BAM complex) in the outer membrane, MDR efflux pumps, and enzymatic degradation/modification, which are known to induce antibiotic resistance (AbR). Here, this work identifies that the AbR mechanisms of MDR Escherichia coli become compromised and sensitive again to conventional antibiotics, when the temperature of infected tissues is elevated to ≈50 °C in situ. This thought is realized by the microwave‐driven poly(lactic‐co‐glycolic acid) microparticles that may effectively convert electromagnetic radiation to thermal energy. The microwave hyperthermia (MWH) therapy not only interrupts the essential surface‐exposed BamA protein of the BAM complex, but also enhances the permeability of the outer membrane and inhibits the action of MDR efflux pumps. MWH also impairs the hydrogen bond interaction between the catalytic residues of bacterial enzymes and functional groups of antibiotic molecules. Lastly, this work demonstrates these combined inhibitors can revitalize the bactericidal effects of conventional antibiotics in MDR Escherichia coli‐associated deep tissue infections.

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Minimizing treatment-induced emergence of antibiotic resistance in bacterial infections

Cited by 156 publications

References 37 publications

Within-patient evolution of plasmid-mediated antimicrobial resistance

Within-patient evolution of plasmid-mediated antimicrobial resistance

Good microbes, bad genes? The dissemination of antimicrobial resistance in the human microbiome

Reversing Multidrug‐Resistant Escherichia coli by Compromising Its BAM Biogenesis and Enzymatic Catalysis through Microwave Hyperthermia Therapy

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